Abstract
Background
Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome.
Methods
We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently.
Results
We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts.
Conclusion
S. haematobium induces distinct alterations in the host’s immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.
Author summary
The parasitic trematode S. haematobium affects 110 million people worldwide. Many studies have described the effects of schistosome infections on humans and animals, but data focusing solely on S. haematobium infections, which cause urogenital schistosomiasis are scarce. Our goal was to evaluate, in a systematic manner, how S. haematobium infection affects the immune system, gene expression and microbiome of the host. These effects are important because they could lead to increased risk of infections, such as HIV, and bladder cancer. We screened 3,177 studies for potential relevance and included 94 of them in this review. Our analysis showed that S. haematobium infection profoundly alters the immune system with a mixed pro-inflammatory and anti-inflammatory response, though with a predominant type 2 immune phenotype and increased regulatory cells. We further found consistent evidence that it impairs local mucosal epithelial barrier integrity, promotes cellular transformation with pro-oncogenic changes in the host, and is associated with microbial alterations in urine, stool, and genital tracts. We discuss how these findings might be interpreted, and the additional research needed, to improve our understanding of S. haematobium pathophysiology and ameliorate the potential sequelae of S. haematobium infection, such as increased viral infections and cancer.
Introduction
Schistosoma haematobium (Sh) is a parasitic trematode affecting over 110 million people worldwide, disproportionately infecting the world’s poor, who suffer from limited access to clean water and adequate healthcare [1–4]. Adult Sh worms reside predominantly in the veins surrounding the genitourinary tract and release eggs that can become entrapped in genitourinary and reproductive tract organs, causing urogenital schistosomiasis. Schistosome eggs are highly immunogenic and provoke local irritation, inflammation, including granulomatous disease, and fibrosis in the affected tissue leading to chronic symptoms, morbidity, and even organ failure and death. Sh eggs that become lodged in the genital tract can result in female or male genital schistosomiasis, while those in the urinary bladder are categorized as Class A carcinogens, contributing to the development of squamous cell carcinoma in the bladder [2].
Overall, Sh infection leads to approximately 1.5 million disability-adjusted life years (DALYs) lost annually [5]. Not included in these DALY calculations is the increasing evidence suggesting that Sh may additionally contribute to DALYs lost through its association with increased susceptibility to secondary infections, including HIV, HPV, and other sexually transmitted infections [6–12]. Moreover, a previously infected host is not immune against reinfection. Hence, individuals living in endemic areas frequently become reinfected with Sh after successful treatment with praziquantel (PZQ) [13] and can experience additional DALYs lost after reinfection. It remains unknown why the human host does not generate a sterilizing immune response upon reencountering Sh. To date, there is no active vaccine against schistosome infections.
Sh is the leading risk factor for bladder cancer in Sh endemic countries with the highest incidence in the Middle East and Africa [14–16]. Carcinogenesis is a complex process resulting from the accumulation of multiple genetic and epigenetic changes including activation of oncogenes, inactivation or loss of tumor suppressor genes, and alterations in apoptotic gene products. These changes can alter cell proliferation of the urothelium and ultimately lead to urothelial transformation [14]. Sh-associated bladder cancer is largely thought to be due to the combination of changes in gene expression plus the chronic inflammation caused by Sh eggs lodged within the bladder tissue.
Schistosome infection also has been reported to affect composition of the human microbiome across a variety of sites, including genitourinary and gastrointestinal tracts [17]. In addition to infections, other factors that influence the composition of the microbiome include inheritance, mode of birth, diet, including malnutrition and breastfeeding, environment, geographical locations, hormonal changes, antimicrobial exposures, and age-related changes throughout child- and adulthood, among many others [17–23]. A mounting number of studies demonstrate that the microbiome influences the immune system, gene expression, and the development of human pathology including cancer and immune mediated diseases [17,24]. Infections, including parasitic infections such as Sh, may directly affect the composition of the microbiome, and thereby then indirectly affect the host immune phenotype [25,26]. Identifying the links between the microbiome and Sh infection may provide prophylactic or therapeutic tools to improve human health [17].
Critically, within schistosome studies, most knowledge to date is derived from studies focusing on S. mansoni and other Schistosoma species despite Sh being the most prevalent schistosome species worldwide. The pattern of immune response, alterations in gene expression or microbiome likely differ from that in Sh infection because the bladder and reproductive tract represent immunologic, genetic and microbiome environments distinct from that of the gastrointestinal tract or liver, which are affected during infections with other Schistosoma spp. A comprehensive analysis of the pathophysiology leading to increased secondary infections or bladder cancer in the setting of Sh infection has not been performed. Gaining a deeper comprehension of these factors could provide valuable insights into the fundamental processes involved and could provide novel targets for treatment and prevention.
To fill this gap, we conducted a rigorous systematic review that aimed to summarize concisely the current knowledge on immune, gene, and microbiome alterations of the host in the setting of Sh infection. We sought to consolidate data to enhance our understanding of the specific pathology occurring during this parasitic infection, bringing together disparate immunological, molecular, and microbial findings from an array of human and animal studies.
Results
Titles and abstracts of 3,177 studies were screened after which 398 full-text papers were assessed for inclusion. A total of 105 studies were included for extraction, and 11 of the 105 were excluded based on the quality assessment using the Downs and Black checklist (Fig 1) [27]. The 11 studies that did not meet Downs and Black criteria of “fair” or better quality are reported in S1 Table. The remaining 94 studies examined effects of schistosome in 3 categories: immune system (N = 66), gene expression (N = 26), and microbiome (N = 6). Each category is discussed in the following sections. Of note, 4 studies reported both on effects of Sh infection on the immune system and gene expression, and in these instances the studies were each cited in the relevant section.
Fig 1. PRISMA flow diagram of systematic review.
The host’s immune response to Sh infection is dynamic with an initial Th1 predominate response to the acute Sh infection followed by a shift to a Th2 predominate response that also includes T regulatory cells (Tregs), B regulatory cells (Bregs), and alternatively activated macrophages (AAM) [28]. This shift to a Th2 predominate response is thought to explain why individuals infected with Sh have poorer immune responses to viruses, as well as higher risk of developing bladder cancer [29,30]. Most studies included in this review focused on the consequences of chronic Sh infection in humans living in Sh-endemic regions. We begin with studies focused on the host’s immune system, followed by those on gene expression, and lastly microbiome. Table 1 outlines the organization of the results section.
Table 1. Overview of the organization of results.
| Heading | Subheadings |
|---|---|
| S. haematobium infection and the host immune system |
Systemic immune responses to Sh infection in humans S. haematobium infection and systemic host chemokine and cytokine immune responses in humans - Systemic cytokine responses to Sh infection - Variation in cytokine responses to Sh by age - Variation in cytokine responses to Sh infection by genitourinary pathology and infection intensity - Variation in cytokine responses to Sh infection by sex - S. haematobium infection and the systemic host cytokine immune response in humans after praziquantel therapy - Overall synthesis of cytokine studies in Sh infection Systemic innate immunity S. haematobium infection and the host innate immune response in the systemic circulation in humans - Dendritic cells - Monocytes - Granulocytes - Innate lymphoid cells Systemic adaptive immunity S. haematobium infection and host systemic lymphocytic proliferation in humans S. haematobium infection and host T cell immune response in the systemic circulation in humans - CD4+ and CD8+ T cells - Memory T cells - Th1 and Th2 cells - Th17 cells - T regulatory cells - T cell marker expression - Overall synthesis of T cell studies in Sh infection S. haematobium infection and host B cell immune response in the systemic circulation in humans S. haematobium infection and the host local genitourinary tissue immune response in humans - Overall synthesis of immune studies in Sh infection on local tissue S. haematobium infection and the local tissue host immune response in patients with bladder cancer - Overall synthesis of Sh infection and the local tissue host immune response in patients with bladder cancer Experimental models to study effects of Sh infection on immune response - Overall synthesis of experimental immune studies in Sh infection |
| S. haematobium infection and host gene expression |
S. haematobium infection and host mucosal gene and protein expression in S. haematobium associated bladder cancer - Overall synthesis of gene expression studies in Sh infection and bladder cancer S. haematobium infection and mucosal gene expression of the host S. haematobium infection and systemic gene expression in blood - Overall synthesis of systemic gene expression studies in Sh infection Experimental models to study S. haematobium infection and host gene, protein expression, and cell cycle dynamics. - Overall synthesis of experimental gene expression studies in Sh infection |
| S. haematobium infection and the host microbiome |
S. haematobium infection and the host microbiome. - Overall synthesis of microbiome studies in Sh infection |
S. haematobium infection and the host immune system
We begin by examining studies of the systemic immune responses to Sh infection in humans categorized into studies focusing on cytokines (N = 27), innate immunity (N = 12), and adaptive immunity (N = 26). We then review studies of local tissue immune responses to Sh infection in humans separating studies on humans without (N = 6) and with bladder cancer (N = 3), and end with animal and other experimental models (N = 8), and how these fit with observations from humans. For studies that investigated multiple aspects of the immune response, such as cytokines and cellular changes, each is referenced twice in the relevant section.
Systemic Immune Responses to Sh Infection in Humans
The immune response to schistosome infections is multifaceted and, as with other pathogens, is mediated by both cytokines and chemokines. These molecules orchestrate both innate and adaptive immune responses, serving both as regulators and amplifiers, and may directly or indirectly be involved in pathophysiology (Box 1). CD4+ T helper (Th) cells produce a variety of cytokines that can be grouped based on the cells they are associated with, including Th1, Th2, Th17, and regulatory T cell cytokines. The type 2 immune response associated with chronic schistosome and other helminth infections is marked by the release of Th2-linked cytokines, which promote wound healing and worm expulsion while dampening inflammation [31–35].
Box 1 Overview of cytokines and chemokines
Cytokines and chemokines are a diverse group of molecules that play a crucial role in coordinating both innate and adaptive immune responses to pathogens. They can be categorized into two functional groups: pro- or anti-inflammatory cytokines, although some overlap exists. Cytokines primarily originate from immune cells but can also be generated by non-hematopoietic cells including epithelial cells (36).
Th1 cytokine family:
Mediate pro-inflammatory responses important for immune responses to pathogens.
Main cytokines are IFN-γ and TNF- α.
IFN-γ is a key mediator of inflammation in response to invading pathogens, particularly bacteria and viruses, and is produced by Th1 cells and other cell types including Natural Killer (NK) cells.
Th2 cytokine family:
Mediate host protection during parasitic infections through enhancing tissue repair, control of inflammation, and helminth expulsion.
Play significant roles in allergic-inflammatory immune responses, inducing eosinophils, basophils, mast cells, and macrophages.
Can counteract the Th1 cytokines since they are important for anti-inflammatory response and have a role in dampening excessive inflammation which can lead to uncontrolled tissue damage and/ or autoimmune disease.
A Th2 dominant immune phenotype counteracts Th1 microbicidal action, and therefore a balance between Th1 and Th2 response is critical.
Main cytokines are IL-4, IL-5, IL-10, IL-13, and IL-33.
IL-4 and IL-13 can additionally stimulate fibroblasts to produce collagen.
IL-13 plays a pro-fibrotic role in the liver during S. mansoni infection.
Overlapping Th1 and Th2 cytokine IL-2:
IL-2 is predominantly produced by activated CD4+ T cells of either the Th1 or Th2 subset.
IL-2 is pertinent for the differentiation of CD4+ and CD8+ T cells into effector and memory T cell subsets following antigen-mediated activation, and it is also crucial for the induction and maintenance of Tregs.
IL-2 can have pro- or anti-inflammatory properties depending on the immune milieu.
Immunosuppressive cytokines:
IL-10 and TGF-β mediate the immune suppressive function of Tregs and can suppress immune responses of any cell type.
Pro-inflammatory cytokines and chemokines, not part of the Th1 family:
Important for immune activation against invading pathogens.
The IL-1 cytokine family, such as IL-1-α and IL-1-β, regulate inflammation by controlling a variety of innate and adaptive immune processes, including acting as leukocytic endogenous mediator and inducing acute-phase proteins and lymphocyte activation factor.
IL-6 is central to host defense and is a potent inducer of inflammation and acute phase proteins.
IL-15 is pertinent in anti-pathogen defense by promoting NK and NK T cell development and memory CD8+ T cell function.
IL-18 is a pleiotropic cytokine functioning as both a potent inducer of inflammation and an inducer of host defense against pathogens regulating innate and acquired immunity.
IL-17 plays a central role in protective immunity against a variety of bacterial and viral pathogens, and promotes pathogenic cytokines in T cell-mediated autoimmune disease pathology. IL-17 can be produced by multiple cell types, including Th17 cells, CD4+ and CD8+ T cells, NK and NK T cells.
IL-21 plays a key pro-inflammatory role in stimulating differentiation of B cells, promoting anti-viral and anti-tumor effects of CD8+ T cells, and inducing Th17 cells which secrete IL-17, recruit neutrophils, and link innate and adaptive immunity. It is produced by T cell subsets and NK T cells.
IL-23, produced by inflammatory myeloid cells, stimulates the development of Th1 cell and Th17 cell responses.
Monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates migration and infiltration of monocytes/macrophages.
Monocyte chemoattractant protein-3 (MCP-3) is a pluripotent chemokine and can activate all types of leukocytes.
Macrophages secrete the chemokine macrophage Inflammatory Protein-1a (MIP-1a) to elicit effects including recruiting inflammatory cells, promoting wound healing, suppressing stem cells, and sustaining effector immune responses.
S. haematobium infection and systemic host chemokine and cytokine immune responses in humans
Systemic cytokine responses to Sh infection
In total, 16 studies assessed systemic cytokine changes in Sh infections (Table 2), with an additional 10 studies investigating cytokine responses following PZQ treatment (Table 3). Many of these studies used various antigens (Box 2) to stimulate cells and quantify responses.
Table 2. S. haematobium infection and systemic host chemokine and cytokine immune responses in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Overall conclusion |
|---|---|---|---|---|---|---|
| Antony et al 2015 (64) | Nigeria | 359 | F (44%) | 2–80 | ↑ IL-6 | IL-6 was elevated in individuals with Sh infection. |
| *Ateba-Ngoa et al 2015 (60) | Gabon | 125 | F (49%) | 6–16 | In response to TLR stimulation: ↑ MCP1-MCAF, MIP-1α, IL-5, Il-10, and IL-13 ↓ IFN-γ and TNF-α |
PBMCs of individuals with Sh infection had elevated macrophage-released chemokines (MCP1-MCAF/MIP-1α), and Th2 cytokines, together with decreased pro-inflammatory cytokines (INF-γ, TNF-α) in response to TLR stimulation, as compared to individuals without infection. |
| Bustinduy et al 2015 (65) | Kenya | 790 | F (50.5%) | 2–19 | ↑ IL-6 at 11- 12yo ↑ IL-10 at 13- 14yo = TNF-α |
Cytokine response was dependent on age of the individuals with Sh infection individuals. IL-6 was elevated in individuals with Sh infection aged 11–12, while IL-10 was only elevated in individuals with Sh infection aged 13–14 compared to individuals without Sh infection. |
| Grogan et al 1998 (68) | Gabon | 12 | F (58%) | median 11 | In response to IL-10 blockade: ↑ IFN-γ (in response to AWA) ↑ Lymphocyte proliferation (with and without AWA stimulation) |
IL-10 suppressed IFN-γ production and lymphocyte proliferation in individuals with Sh infection. |
| Imai et al 2011 (61) | Zimbabwe | 95 | F (% not documented) | 1–5 | ↑ IL-5, IL-10, and IFN-γ | Individuals with Sh infection had a mixed Th1 and Th2 cytokine response. |
| Kasambala et al 2023 (66) | Zimbabwe | 136 | F (46%) | Median 51mo | ↑ IL-6 and TNF-α ↓ IL-10 = IL17A = TGF-β |
PSAC with Sh infection had higher inflammatory markers, IL-6 and TNF- α, compared to PSAC without infection. |
| *King et al 1996 (69) | Egypt | 38 | F (5%) | 6–30 | In response to SWAP and SEA: ↑ IL-10 In response to IL-10 antibody blockage in individuals with Sh infection after SWAP/ SEA stimulation: ↑ IFN-γ ↑ Lymphocyte proliferation |
IL-10 increased in individuals with Sh infection, and blockade of IL-10 led to an increase in IFN-γ and lymphocyte proliferation. |
| King et al 2001 (74) | Kenya | 37 | F (30%) | 7–18 | Individuals with infection with and without bladder pathology: ↑ TNF-α spontaneously, and in response to SEA and PPD = IL-4, IL-5, IL-10, and IFN-γ |
TNF-α was elevated in individuals with Sh infection with bladder pathology. |
| *Labuda et al 2020 (58) | Gabon | 79 | Male and female (%, not documented) | School-children | In response to AWA and SEA: ↑ IFN-γ, IL-2, IL-5, IL-10, and TNF-α In response to PHA: = IFN-γ, IL-2, IL-5, IL-10, and TNF-α |
Children with Sh infection produced elevated systemic Th1 and Th2 cytokines in response to Sh antigens, AWA and SEA. |
| *Lyke et al 2006 (59) | Mali | 676 | F (51%) | 4–14 | ↑ IL-6 (only significant in 4–8 yo) ↑ IL-4, IL-10, and IFN-γ = IL-2, IL-5, and TNF-α |
Children with Sh infection had elevated circulating Th1 and Th2 cytokines. |
| Mduluza et al 2001 (57) | Zimbabwe | 4 | Not documented | 10–12 | In response to SEA and AWA: ↑ IL-4:IFN-γ ratio ↑ IL-5:IFN-γ ratio |
Participants with Sh infection had elevated IL4 to IFN-γ and IL-5 to IFN-γ ratios after stimulation with Sh antigens, AWA and SEA. |
| *Meurs et al 2011 (63) | Gabon | 30 | F (42%) | 7–16 | In response to TLR2 stimulation: ↑ TNF-α (TLR2 ligand Pam3) ↑ TNF-α/ IL-10 ratio (TLR2 ligand Pam3 and FSL-1) In response to schistosome SEA and AWA stimulation: ↑ TNF-α/ IL-10 ratio (to AWA) ↑ IL-10 in response (to AWA/ SEA) |
TNF-α response and TNF-α/ IL-10 ratio was higher in individuals with Sh infection upon TLR2 stimulation of PBMCs. IL-10 increased only to AWA and SEA stimulation in individuals with Sh infection but not to TL2 ligand stimulus. |
| Milner et al 2010 (72) | Zimbabwe | 227 | F (not documented) | 6–60 | ↑ IL-2, IL-10, and IL-23 ↓ IL-4, IL-13, and IL-21 Sh infected with low egg burden: ↑ IL-17 and IL-23 |
In a population that was Sh positive, individuals with Sh infection had a mixed Th1 ⁄Th2 systemic cytokines at baseline, while Th2 cytokines dominated in individuals without infection. |
| Mutapi et al 2006 (110) | Zimbabwe | 190 | F (54%) | 6–40 | Compared cytokine response among Sh infected by age group and infection intensity: ↑ IL-4 to SWAP stimulation in 15–16 yo ↑ IL-5 to SWAP and ConA stimulation in 15–16 yo ↑ IL-10 to SWAP stimulation in < 14 yo ↑ IL-10 to ConA stimulation in > 14 yo ↑ IFN-γ to ConA stimulation in 13–14 yo High Sh egg burden: ↑ IL-10 and IL-5 In response to IL-10 antibody blockade: ↑ IL-5 |
Cytokine responses varied by age, infection status, urinary Sh egg burden and by the specific antigen stimulus. |
| Remoué et al 2001 (83) | Senegal | 23 | F (48%) | 35–57 | Women with Sh infection versus men with Sh infection in response to SEA: ↓ TNF-α and IFN-γ ↑ TGF-β and IL-10 ↑ nuclear matrix protein |
Among individuals with Sh infection, the cytokine production to SEA stimulation differed between sexes, with women producing less pro-inflammatory cytokines and more IL-10 and TGF-β which can have pro- and anti-inflammatory properties. |
| Van der Kleij et al 2004 (62) | Gabon | 25 | F (40%) | 8–15 | = Monocytes, B cells, and T cells In response to LPS: ↓ IL-8 and IL-10 ↓ IL-6 (trend) and TNF- α (trend) In response to schistosomal PS: ↓ IL-8) and TNF- α ↓ IL-10 (trend) and IL-6 (trend) In response to schistosomal GL: ↑ IL-6 ↑ IL-8 (trend) = TNF- α and IL-10 |
Cytokine responses varied in individuals with Sh infection and were dependent on the antigen used to stimulate PBMCs. Cytokine response (IL-8, IL-10, IL-6, and TNF- α) was blunted in response to LPS in individuals with Sh infection. |
Sh = S. haematobium, PS = schistosomal phosphatidylserine, GL = Glycolipid, LPS = Lipopolysaccharide, SEA = soluble egg antigen, AWA = adult worm antigen, Mo = months, PSAC = pre-school aged children, yo = year old
*Studies included participants with additional parasitic infections.
Table 3. S. haematobium infection and the systemic host cytokine immune response in humans after praziquantel therapy.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| Bourke et al 2013 (87) | Zimbabwe | 72 | F (44%) | 5–17 | N/A | In response to SEA stimulation: ↓ TNF-α, IL-6, IFN-γ, IL-2, IL-8, IL-12p70, IL-21, and IL-23 In response to CAP stimulation: ↓ IL-8, IL-10, and IL-13 ↓ IL-23 In response to WWH stimulation: ↑ IL-21 ↓ TNF-α and IL-6 In response to any schistosome antigen (SEA, CAP, WWH) stimulation: = IL-4, IL-5, and IL-17A 6 weeks after treatment |
A pro-inflammatory cytokine pattern was released in response to SEA, a mixed response of pro- and anti-inflammatory cytokines to CAP stimulation and a less inflammatory cytokine response to WWH stimulation in prior individuals with Sh infection who underwent PZQ treatment. |
| Grogan et al 1998 (75) | Gabon | 47 | Not documented | Children- adults | N/A | Individuals with prior Sh infection who received PZQ 2 years prior comparing individuals with reinfection vs individuals without infection: ↓ IL-4 and IL-5 (in response to SEA, AWA) ↓ IFN-γ (in response to SEA, AWA) ↓ Lymphocyte proliferation (with AWA stimulation only) |
Individuals with prior Sh infection who became reinfected had decreased Th1 and Th2 cytokines in response to Sh antigens, SEA and AWA. |
| Khalil et al 1999 (92) | Egypt | 108 | F (0%) | 10–45 |
Sh-reinfected: ↑ IL-4 |
↓ IL-4 12 months after treatment |
IL-4 increased during active Sh infection and decreased after treatment. |
| Mduluza at al 2003 (88) | Zimbabwe | 40 | Not documented | 7–16 | Population with high Sh endemicity, in response to SEA and SWAP: ↑ IFN-γ, IL-4, and IL-5 = IL-4 to IFN-γ ratio = IL-5 to IFN-γ ratio ↓ IL-10 to IFN-γ ratio Population with low Sh endemicity, in response to SEA and SWAP: ↑ IFN-γ = IL-4 and IL-5 = IL-4 to IFN-γ ratio = IL-5 to IFN-γ ratio = IL-10 to IFN-γ ratio |
Individuals with prior Sh infection with reinfection compared to Sh without reinfection after PZQ therapy, in response to SEA and SWAP: ↑ IL-4:IFN-γ ratio ↑ IL-5:IFN-γ ratio ↑ IL-10:IFN-γ ratio ↑ IL-4 and IL-5 ↓ IFN-γ 12 and 18 months after treatment |
Cytokine responses in individuals with Sh infection varied between high and low Sh endemic areas of residence. Th1-like response dominated during Sh infection while the Th2-like responses dominated post treatment in Sh-uninfected individuals. |
| Medhat et al 1998 (91) | Egypt | 86 | F (0%) | 9–15 | N/A | Individuals with prior Sh infection who became reinfected versus those with prior Sh infection who did not become reinfected after PZQ therapy, in response to SWAP stimulation: ↓ IL-4 and IL-5 ↓ IFN-γ (trend) 12–18 months after treatment |
Individuals with Sh reinfection had lower Th2 cytokines IL-4 and IL-5. |
| Mutapi et al 2001 (71) | Zimbabwe | 602 | Men and women (% F not documented) | 2–86 | ↓ IL-10 (trend) | ↑ IL-10 6 weeks after treatment |
IL-10 was inversely associated with Sh infection and increased post-treatment. |
| Van Den Biggelaar et al 2002 (93) | Gabon | 135 | F (50%) | 5–14 | N/A | Compared cytokine response in individuals with prior Sh infection after zero, one, or multiple PZQ treatment courses after 24 months: All in response to AWA stimulation: Individuals with Sh infection versus without infection without PZQ treatment: ↑ IL-5 ↑ IL-13 (trend) = IL-10 ↓ IFN-γ (trend) Individuals with Sh infection versus without infection after 1 dose of PZQ treatment: ↑ IL-5 ↑ IL-13 (trend) = IL-10 and TGF-β ↓ IFN-γ Individuals with Sh infection versus without infection after multiple doses of PZQ treatment: = IL-5, IL-13, IFN-γ, IL-10, and TGF-β Individuals with Sh infection and without infection after multiple doses of PZQ treatment in comparison to individuals with Sh infection and individuals without infection with no or 1 dose PZQ treatment: ↑ IL-5 24 months after treatment |
Cytokine production varied depending on current Sh infection as well as preceding PZQ treatment. In individuals with Sh infection at 24 month follow up, Th2 cytokines IL-5 and IL-13 were only elevated in individuals who received 0 or 1 dose of PZQ treatment 24 months before. Individuals with Sh infection after 0 or 1 dose of PZQ treatment had lower IFN-γ in comparison to the individuals without infection at 24 month follow up. Participants who received multiple PZQ courses had the highest IL-5 levels at 24 month follow up regardless of Sh status in comparison to the other 2 treatment arms (0 or 1 dose PZQ treatment). |
| Wilson et al 2013 (84) | Mali | 47 | F (60%) | 5–39 | N/A |
24 hours after treatment ↑ IL-5 9 weeks after treatment ↓ IL-5 and IL-13 ↑ IL-33 = sST2 (IL-33 receptor) ↑ Intracellular IL-5 in eosinophils ↑ Intracellular IL-13 in eosinophils |
IL-5 increased 24 hours post-PZQ treatment. In individuals with prior Sh infection, IL-33, eosinophilic IL-5 and IL-13 increased 9 weeks post-PZQ. |
| Wilson et al 2013 (85) | Mali | 326 | F (57%) | 5–40 | N/A | ↑ IL-5 and IL-13 = IL-4 24 hours after treatment |
IL-5 increased after 24 hours post-PZQ treatment. |
| *Zinyama-Gutsire et al 2009 (89) | Zimbabwe | 379 | F (80%) | 17–62 | ↑ MIP-1α | ↓ MIP-1α 3 months after treatment |
Individuals with Sh infection had elevated systemic MIP-1α which decreased post-PZQ. |
Sh = S. haematobium, SEA = schistosomal egg antigen; CAP = cercariae; WWH = adult worm antigen; MIP-1α = macrophage inflammatory protein-1α
*Studies included participants with additional parasitic infections.
Box 2 Overview of immune cell stimulants
Peripheral blood mononuclear cells (PBMCs) release cytokines through a receptor-mediated cascade, which depends on both the cell type and the specific antigen encountered. Researchers frequently utilize the potential to activate PBMCs using different antigens to examine the cytokine response following antigen stimulation in cells from study participants or in experimental models. This assessment can help ascertain the immune system’s functional response to stimulation by specific or general pathogens.
Using different schistosome antigens from different stages of the parasite life cycle, such as worm antigen or egg antigen, is important because each antigen can elicit a different immune response in the host. This variety helps researchers and clinicians better understand the dynamics of the infection and develop more effective diagnostic tools and treatments. Different antigens may also have varying levels of sensitivity and specificity, making them useful in different contexts or stages of the disease.
Schistosome antigens
Soluble egg antigen (SEA)
Adult worm antigen (AWA)
Soluble adult worm antigen preparation (SWAP)
Schistosome phosphatidylserine (PS)
Mycobacterium tuberculosis antigen
Purified protein derivate (PPD)
Generic antigens
Glycolipid (GL)
Lipopolysaccharide (LPS)
Phytohemagglutinin (PHA)
Pokeweed mitogen (PWM)
Concanavalin A (ConA)
TLR-2 stimulants: FSL-1 and Pam3
TLR-9 stimulants: CpG and R848
In an earlier study examining human peripheral blood mononuclear cells (PBMCs) from two Zimbabwean children with Sh eggs in urine, stimulation with schistosome antigens AWA and SEA led to elevated IL-4 and IL-5 levels and higher ratios of these cytokines to IFN-γ, compared to 2 children without Sh infection [57].
In a similar study, whole blood of 40 children with Sh infection responded to schistosome antigen AWA and SEA stimulation with production of higher levels of Th1 and Th2 cytokines including IFN-γ, IL-2, IL-5, IL-10, and TNF-α, compared to 39 children without Sh infection [58]. PZQ treatment increased the production of IFN-γ, IL-2, IL-5, IL-10, and TNF-α in whole blood of previously infected children in response to schistosome antigens AWA and SEA and also increased production of the immunosuppressive cytokine, IL-10, but not the other cytokines, in response to generic antigen stimulation [58].
Circulating IL-10 and INF-γ were elevated in serum of Malian children with Sh infection, similarly to the stimulation study above alongside IL-4 and IL-6, compared to individuals without Sh infection. In contrast to the stimulation study above, there were no differences seen in IL-2, TNF-α, and IL-5 [59].
A PBMC stimulation study in Gabonese children with Sh infection revealed increased macrophage-released chemokines (MCP1-MCAF/MIP-1α) and Th2-related cytokines such as IL-5, IL-10, and IL-13, with a simultaneous decrease of pro-inflammatory cytokines (IFN-γ, TNF-α) compared to children without Sh infection [60]. Factors like soil-transmitted helminths (STH) [59] and filarial co-infections [60] were similarly distributed among the groups. Nevertheless, co-infections in these two studies might have influenced the results.
A factor analysis study in Zimbabwean children similarly found that a composite variable representing IL-5, IL-10, and IFN-γ increased with age and was positively associated with current Sh infection as well as with past Sh exposure determined by the presence of Sh-specific antibodies in serum [61]. Of note, pro-inflammatory IFN-γ results were not reported separately.
A study from an area of Gabon by Van der Kleij et al [62] found varying responses of IL-8 and IL-10 depending on the specific antigen used for stimulation, with lower levels after lipopolysaccharide (LPS) and schistosomal phosphatidylserine stimulation in individuals with Sh infection versus individuals without Sh infection, but higher IL-8 in response to the schistosome glycolipid (GL) antigen. Notably, PBMC stimulation in the presence of a toll-like receptor 2 (TLR2)-blocking antibody decreased the cytokine responses induced by schistosomal phosphatidylserine for IL-10, IL-8, and IL-6 [62]. Similarly, Meurs et al [63] found elevated IL-10 and TNF-α levels in Gabonese children with Sh infection after stimulation of PBMCs with TLR2-specific and schistosome antigens SEA and AWA, compared to children without Sh infection [63]. Meurs et al [63] selected children with Sh infection and children without infection from the same area, while the participants without Sh infection in van der Kleij’s study were recruited from a nonendemic neighboring semi-urban area and were more likely truly Sh-uninfected [62]. Both studies suggest that the immune response to Sh operates via TLR ligand signaling [62,63].
Five studies demonstrated higher systemic levels of IL-6, which integrates the immune defense against infections [47], in individuals with Sh infection versus individuals without Sh infection [59,62,64–66]. Serum IL-6 levels were also higher among those with active infections than those with positive Sh serologies without active infection [64] and in individuals with Sh infection with urinary tract pathology [67], supporting a likely role of IL-6 in the pathogenesis of urogenital schistosomiasis.
IL-10 has both immunomodulatory and anti-inflammatory properties [43] that appear to be important during Sh infection. Two studies showed that blockade of IL-10 with monoclonal antibodies of isolated PBMCs led to increased IFN-γ production and enhanced lymphocyte proliferation following stimulation with schistosome antigens SEA and AWA in people with Sh infection [68,69]. A Zimbabwean study assessing the cytokine response to AWA stimulation of PBMCs revealed that IL-10 was most strongly correlated with Sh infection intensity, and that participants with high intensity infection also tended to produce lower IL-5 levels [70]. The addition of IL-10 blocking antibodies to PBMCs isolated from individuals with Sh infection led to an increase in IL-5 response [70], suggesting that IL-10 may be exerting its modulatory effect by down-regulating IL-5 production. In contrast, in a large Zimbabwean cohort, IL-10 levels were lower in plasma of those with Sh infection, and subsequently increased when measured 6 weeks after PZQ treatment [71]. Similarly, serum of pre-school aged children with Sh infection had lower IL-10 levels compared to individuals without Sh infection, and had higher pro-inflammatory IL-6 and TNF-α [66]. In conclusion, the diverse findings on IL-10 in Sh infection highlight its complex role in the immunopathogenesis of Sh infection, with studies indicating both modulatory and anti-inflammatory effects on cytokine responses, and dynamic changes in systemic levels following treatment.
In general, Sh infection appears to result in systemic alterations in an array of cytokines and chemokines, with most studies describing an increase in the Th2 cytokines IL-4, IL-5, and IL-10, as well as Th1 cytokines IL-6 and IFN-γ (Fig 2). This mixed pro-inflammatory and anti-inflammatory response observed in Sh infection highlights the complexity of immune responses to this parasite. While the prevailing notion of a type 2 immune state is confirmed here, this synthesis further identifies a co-existing pro-inflammatory environment in chronic Sh infection.
Fig 2. Systemic cytokine and chemokine changes in the setting of S. haematobium infection in humans.
Overview of results of the 14 studies assessing systemic cytokine trends at baseline or after antigen stimulation in individuals with Sh infection individuals of the total 27 studies investigating systemic cytokines in this review. Data on counts of the reported cytokines were collected. Sh infection was associated with an increased release of systemic Th2 cytokines (IL-4, IL-5, Il-10): Four out of 5 studies (80%) reported an increase in IL-4, 4 out of 5 studies (80%) reported an increase in IL-5 and 8 out of 12 studies (67%) showed an increase in IL-10 in the setting of Sh infection. The regulatory cytokine IL-2, which is pertinent for induction and maintenance of T cell subsets including Tregs, was elevated in 2 out of 3 studies (67%) but also unchanged in 2 out of the 3 studies (67%) in individuals with Sh infection depending on which specific antigen was used. Increased proinflammatory cytokines (IL-6, IFN-γ, IL-23) were associated with Sh infection: Five out of 6 studies (83%) reported increased IL-6 levels, 4 out of 6 (67%) reported an increase in IFN-γ and one study reported an increase in IL-23 in the setting of Sh infection. One study (100%) reported an increase in macrophage related inflammatory cytokines MCP1-MCAF and 2 studies (100%) an increase of MIP-1α in individuals with Sh infection. Graph developed using GraphPad Prism.
Variation in cytokine responses to Sh by age
A Zimbabwean study found elevated circulating cytokines IL-2, IL-10 and IL-23 and lower IL-4, IL-13, and IL-21 in individuals with Sh infection aged 6–60 years compared to individuals without Sh infection [72]. Cytokine patterns varied with age, with increasing IL-4 and IL-10 levels, and decreasing IL-5 levels in plasma, in those with Sh infection as age increased [72]. Notably, all participants had detectable parasite-specific antibodies, particularly IgM reflecting recent schistosome exposure, but only those with Sh eggs in urine were considered individuals with Sh infection [72]. Given the suboptimal sensitivity of urine microscopy, particularly among females, some infected participants may have been misclassified as individuals without Sh infection [73]. In agreement with studies above, this cross-sectional study shows that individuals with Sh infection have mixed Th1 /Th2 systemic cytokines across the lifespan, while Th2 cytokines dominated in uninfected people who were Sh-seropositive, indicating past exposure to Sh [72].
In another Zimbabwean study, responses to antigen stimulation varied by age of the person with Sh infection. Adolescents with Sh infection aged 15–16 years showed the highest IL-4 and IL-5 responses to SWAP stimulation of whole blood, and similarly IL-5 peaked in this age group after ConA stimulation [70]. IFN-γ levels peaked at age 13–14 years in response to generic antigen stimulation, but not SWAP stimulation. IL-10 was highest in serum of children in response to SWAP but was lower in participants older than 14 years and decreased further with age. In contrast, stimulation with a ConA led to IL-10 levels that were lowest in children aged 6–12 years with an increase starting in aged 13–14 years, peak at age 15–16 years, and a decline in older participants though those over age 16 years still had higher levels than children aged 6–12 years [66].
In younger children, TNF-α was higher in serum of pre-school aged children with Sh infection, while IL-6 was only found to be higher in children aged 11–12 years in a second study of children aged 2–19 years [65]. Consistent with the Mutapi study above, Bustinduy et al also reported increased IL-10 in 13–14-year-olds with Sh infection compared to their age-matched counterparts without Sh infection [65]. These studies uniformly emphasize the age-related variability in cytokine response.
Variation in cytokine responses to Sh infection by genitourinary pathology and infection intensity
A study in Kenyan individuals with Sh infection and concomitant bladder pathology assessed by ultrasonography reported a 12-fold higher serum TNF-α production at baseline and 13-fold higher production in response to schistosome and purified protein derivative antigen stimulation than in persons with Sh infection without bladder pathology [74]. This implies that pro-inflammatory TNF-α may contribute to the genitourinary damage during Sh infection [74]. Conversely, in a Gabonese cohort, Sh urinary egg burden correlated inversely with IFN-γ levels in PBMCs after AWA or SEA stimulation from individuals who developed Sh reinfection two years after PZQ treatment, suggesting a lower pro-inflammatory immune environment in those with the highest Sh burden [75].
Variation in cytokine responses to Sh infection by sex
Sex hormones affect immune function and lead to differences in the immune phenotype and disease response between women and men [76,77]. Furthermore, sex differences in immune response also vary over the lifespan and with reproductive status, which is particularly pronounced in women with fluctuations due to the menstrual cycle as well as during pregnancy, breastfeeding, and menopause [78–82]. In a Senegalese cohort, women with Sh infection produced lower levels of TNF-α and IFN-γ following SEA stimulation of PBMCs, while they produced more TGF-β and IL-10 and had higher expression of the apoptosis marker nuclear matrix protein, compared to men with Sh infection with comparable egg burdens and schistosome circulating anodic antigen (CAA) levels [83]. Although this was a small study consisting of 23 participants, these findings suggest that women with Sh infection produce less pro-inflammatory Th1 cytokines, and more anti-inflammatory IL-10 than men. Women’s higher production of TGF-β, which is mainly produced by fibroblast and epithelial cells, may have either pro- or anti-inflammatory immune effects [44,45].
S. haematobium infection and the systemic host cytokine immune response in humans after praziquantel therapy
Wilson et al conducted two cohort studies comparing cytokine response in plasma of Malian individuals with Sh infection at time-points 24 hours after PZQ treatment and 9 weeks post-treatment [84,85]. In one cohort, systemic IL-5 increased 24 hours post-PZQ, around the time of adult worm death, but decreased at 9 weeks, while IL-33 was higher at 9 weeks post-treatment [84]. Further, intracellular eosinophil IL-5 and -13 both increased at 9 weeks, and sST2 (IL-33 receptor) was associated with intracellular IL-13, suggesting a role of IL-33 in the human response to Sh infection [84]. In the second Malian cohort, IL-5 increased 24 hours post-treatment, as did IL-13 in plasma [85]. Eosinophils increased at 9 weeks, associated with an IL-5 boost and pre-treatment infection intensities. Of note, 13.9% of a subset of participants who provided stool were found to have concomitant S. mansoni infection [85]. Together, these studies suggest a time dependent cytokine response post-PZQ treatment likely due to an initial surge of Sh antigen release from dying adult worms which diminishes over time [86].
Cytokine production after PZQ treatment also appears to differ between children and adults and with specific antigen stimulation. In those with prior Sh infection, stimulation of whole blood cultures with egg-specific antigen SEA led to a pronounced pro-inflammatory cytokine pattern with elevated TNF-α, IL-6, IL-8, IFN-γ, IL-12p70, IL-21, and IL-23 6 weeks post-treatment, while cercariae-specific antigen CAP led to a mixed pattern of pro- and anti-inflammatory cytokines with elevated IL-8, IL-13, and IL-10 and lower IL-23 [87]. Stimulation with adult worm-specific antigen WWH evoked the lowest inflammatory responses, reflected by low IL-6 and TNF-α and elevated IL-21 which can have pro- and anti-inflammatory properties [87], likely reflecting the low immunogenic potential of adult worms while they are living in the bloodstream [1]. In the same study, a schistosome egg-specific pro-inflammatory cytokine profile and adult worm-specific Th-2 and Th-17-associated cytokine profiles were associated with lower risk of Sh reinfection. Overall, Bourke et al report increased inflammatory, Th1 and Th17 cytokines after PZQ after egg-specific stimulation, while Th2 cytokines were unchanged [87].
Mduluza et al [88] assessed cytokine responses in PBMCs in response to schistosome antigens SEA and SWAP in two Zimbabwean cohorts residing in a high or low Sh endemic area and with or without Sh infection. Individuals with Sh infection from both areas produced higher levels of IFN-γ while IL-4 and IL-5 were only elevated in individuals with Sh infection from the high endemic area compared to those without Sh infection [88]. PZQ treatment decreased the IFN-γ response, while IL-4 and IL-5 remained elevated in both cohorts compared to persons without Sh infection. At enrollment there was no difference in cytokine ratios, while ratios increased towards a Th2 phenotype 12 and 18 months post-PZQ therapy in those who remained uninfected versus those who became reinfected in areas of both high and low endemicity. Specifically, those who became reinfected showed a more pronounced Th1 phenotype [88]. A weakness of this study was lack of data analysis by host sex, despite its potential impact on the immune response. This study highlights a mixed immune response to Sh infection and the putative role of Th2 immunity in Sh resistance.
The pro-inflammatory chemokine macrophage inflammatory protein-1 (MIP-1α) was elevated in plasma of individuals with Sh infection compared to Zimbabwean adults without infection, correlated with urinary Sh egg counts, and decreased 3-months post-PZQ therapy [89]. While MIP-1α can enhance expression of HIV entry molecules CCR5 and CXCR4 on HIV target cells such as CD4+ T cells [90], MIP-1α did not vary by HIV infection status in this Zimbabwean study. This is pertinent since some studies have shown associations between HIV and Sh infections [6–8,12].
In a Gabonese cohort, Sh reinfection was associated with lower IL-4, IL-5, and IFN-γ levels after schistosome stimulation with AWA and SEA of PBMCs compared to those who remained uninfected 2-years after PZQ treatment, suggesting that these lower cytokine levels could possibly predict risk for reinfection [75]. Of note, this study did not document sex distribution, nor was age clearly defined. Similarly, PBMCs of Egyptian male children with previous Sh infection who had become reinfected 12–18 months post-PZQ had lower IL-4 and IL-5 production in response to schistosome antigen SWAP, compared to male children who were not reinfected. Depletion of CD4+ T cells abrogated this response, suggesting that they are the source of these cytokines [91]. These two studies, combined with the Mduluza study discussed above, consistently suggest that an impaired type 2 response post-treatment is associated with susceptibility to reinfection. In contrast, in an Egyptian cohort of male children and adults, higher IL-4 levels were found in individuals who became reinfected compared to those who did not. Further, IL-4 was associated with higher egg burden and remained persistently elevated even after treatment [92].
A study in Gabon showed that plasma cytokine levels varied in individuals with prior Sh infection after two years depending on if they received treatment and how many PZQ treatment courses they received [93]. Individuals who were untreated and those who received a single dose of PZQ had higher IL-5 levels and a trend towards higher IL-13 levels in response to schistosome antigen AWA compared to people without infection at the two-year follow up who had not been treated. Individuals who cleared infection after a single dose of PZQ had the highest IFN-γ, suggesting a potential protective effect of this cytokine. Moreover, repeated treatment led to high IL-5 and low IFN-γ production in response to AWA in comparison to no or single treatment, but was not protective against Sh reinfection. The authors concluded that overall cytokine response to AWA remained altered in previously persons with Sh infection despite treatment [93]. On further analysis, the authors also reported that elevated levels of schistosome-specific IL-10 preceded Sh reinfection, and high levels of IL-5 were associated with hematuria.
Overall synthesis of cytokine studies in Sh infection
Overall, Sh appears to evoke aspects of both pro- and anti-inflammatory responses in the host. Nine Sh studies align with the prevailing hypothesis that a type 2 immune response predominates in most helminth infections [33–35,94], accompanied by an increase in Th2 related cytokines and decrease in Th1 cytokines [57,60,62,63,70,75,92].
Notably, ten other studies showed evidence of pro-inflammatory responses in individuals with Sh infection compared to individuals without Sh infection, including higher IL-6 [59,62,64–66,87], IFN-γ [59,70,88], and pro-inflammatory chemokine MIP-1α [89]. Supporting the complexity of this area, seven other studies have documented a hybrid response which includes pro- and anti-inflammatory cytokine responses [58,59,61,63,66,70,72].
Cytokine responses to PZQ treatment are also complex. Taken together, most studies support a conclusion that a strong Th2 immune response is triggered by dying Sh worms [85]. In the ensuing time after treatment, most studies indicate further immune changes including a continued increase of Th2 cytokines [71,84,85,88,93] and decrease in pro-inflammatory cytokines and chemokines including IFN-γ [88,93] and MIP-1α [89]. It remains to be determined how long this Th2 predominant immune phenotype persists and if it ever reverts to a more balanced Th1/ Th2 phenotype in the absence of further helminth infections. Importantly, higher levels of Th2 cytokines have been linked to reduced likelihood of reinfection, while lower levels correlated with reinfection in two separate studies [75,91]. Additional studies to understand the protective role and duration of Th2 cytokines could have high relevance for infection prevention and elimination.
A caveat to these overall cytokine studies in Sh is the complexity of assessing immune responses in Sh infection. It is not possible to elucidate how long the individual has been infected, nor to account fully for other contributing factors, including age [65,72], sex [83], and infection history both past and current [95]. Further complicating comparisons across studies, varied chemokine and cytokine responses to stimulation by different antigens in different environments may also affect results [62,87]. Indeed, many studies included participants with other parasitic infections, mostly other helminths [59,60,62,69,89] and malaria [63]. These other infectious stimuli likely alter the individual’s immune response, and therefore many findings cannot be attributed to Sh infection alone.
Finally, there are likely significant differences between systemic and local mucosal cytokine production or secretion during Sh infection in the genitourinary tract. It will be critical to increase our understanding of the local tissue immune response to genitourinary tissue damage, which also might increase the risk of acquiring other infections such as HIV [96] or establishing a permissive environment for the development of bladder cancer [30]. The single study that correlated cytokines with organ damage found higher systemic levels of the pro-inflammatory cytokine TNF-α in children with Sh infection with genitourinary pathology assessed by ultrasonography [74]. Additional studies to link cytokine activity with genitourinary pathology are critically needed to understand the tissue immune milieu and strategies to prevent mucosal pathology. It remains to be determined whether a pro-inflammatory immune response occurs in reaction to Sh-induced tissue damage or if it plays a causative role in tissue damage. Longitudinal studies to assess associations between organ pathology and immune responses, as well as effects post-treatment, would provide much needed additional insight.
Accessing tissue samples is more challenging and costly than obtaining peripheral blood, which is likely why most studies concentrate on systemic cytokine responses while trying to relate them to local mucosal processes in the genitourinary tissue, instead of studying cytokine responses directly at the affected organ. Some of these mucosal studies do exist and are discussed in more detail below.
Systemic innate immunity
S. haematobium infection and the host innate immune response in the systemic circulation in humans
A total of 12 studies have assessed changes in innate immune cells seen in Sh infections (Table 4).
Table 4. S. haematobium infection and the host innate immune response in the systemic circulation in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| Appleby et al 2014 (108) | Zimbabwe | 100 | F (59%) | Mean 16.4 (5–>16) |
= Monocytes = CD14 expression by monocytes In > 16 years of age: ↓ CD16 expression by monocytes |
N/A | Individuals with Sh infection had lower expression of the activation marker CD16. |
| Everts et al 2010 (102) | Gabon | 43 | F (21%) | 17–39 | ↓ mDCs and pDCs ↓ HLA-DR expression on mDCs and pDCs In response to LPS stimulation: ↓ IL-6, IL-10, IL-12, and TNF-α by mDCs ↓ MAPK by mDCs = PDL-1 by T cells After co-culture with mDCs from participants with Sh infection: ↓ IL-4 and IFN-γ production by naïve T cells ↓ CD25 expression by naïve T cells |
N/A | Sh infection led to decrease and functional impairment in DCs subpopulations, mDCs and pDCs, leading to T cell hyporesponsiveness in individuals with Sh infection. |
| Hagan et al 1985 (114) | The Gambia | 50 | F (28%) | 8–13 | N/A | ↓ Eosinophils in particpiants with reinfection 12 months after treatment |
Children with prior Sh infection who remained uninfected 1 year after successful PZQ therapy had increased circulating eosinophils compared to reinfected, suggesting a protective effect of eosinophils against Sh reinfection. |
| Kasambala et al 2023 (66) | Zimbabwe | 136 | F (46%) | Median 51mo | = Neutrophils | N/A | Neutrophil counts were similar between PSAC with and without Sh infection. |
| Kleppa et al 2014 (107) | South Africa | 44 | F (100%) | 15–23 | ↑ Monocytes ↑ CCR5+ Monocytes |
↓ CCR5+ Monocytes 7–8 months after treatment |
Individuals with Sh infection had higher circulating monocytes, and increased expression of the HIV entry molecule CCR5, which decreased post-PZQ. |
| Mbow et al 2013 (113) | Senegal | 26 | F (50%) | 5–14 | ↑ Granulocytes, eosinophils in Sh with GU pathology vs without pathology = Absolute neutrophil count |
N/A | GU pathology in individuals with Sh infection was associated with increased granulocytes and eosinophils. |
| Meurs et al 2011 (63) | Gabon | 30 | F (42%) | 7–16 | ↑ Eosinophils (trend) | N/A | Sh infection was associated with eosinophilia, although not statisitically signfificant. |
| Nausch et al 2012 (103) | Zimbabwe | 61 | F (56%) | 5–45 | In all age groups: = pDCs = HLA-DR andCD86 expression on pDcs In 5–10 years of age: ↑ mDCs ↑ HLA-DR expression on mDCs In > 10 years of age: ↓ mDCs = HLA-DR and CD86 expression on mDCs |
N/A | The response of DC populations to Sh infection varied by age with increasd mDC in aged 5–10 and decreased mDC seen only in individuals above age of 10. |
| Nausch et al 2015 (117) | Zimbabwe | 72 | F (54%) | 6–18 | ↓ ILC2 = TSLP and IL-33 In 14–18 years of age: ↑ IL-4, IL-5, and IL-13 associated with increased Sh infection |
↑ ILC2 ↑ TSLP 6 weeks after treatment |
Sh infection was associated with lower circulating ILC2 levels which were restored after PZQ therapy. |
| Shariati et al 2001 (207) | Malia, Nigeria | 33 | F (3%) | 19–37 | ↑ Eosinophils | N/A | Sh infection was associated with peripherial eosinophilia. |
| Wilson et al 2013 (84) | Mali | 47 | F (60%) | 5–39 | N/A | = Eosinophils 9 weeks after treatment |
There was no difference in eosinophils in individuals with prior Sh infection d pre- or post-PZQ. |
| Wilson et al 2013 (85) | Mali | 326 | F (57%) | 5–40 | N/A | ↑ Eosinophils 9 weeks after treatment |
Eosinophils increased in individuals with prior Sh infection 9 weeks post-PZQ. |
Sh = S. haematobium, DCs = dendritic cells, mDCs = myeloid dendritic cells, pDCs = plasmacytoid dendritic cells, TLR = toll-like receptor, PSAC = pre-school aged children, MAPK = Mitogen-activated protein kinase
Dendritic cells
Antigen-presenting dendritic cells (DCs) are among the first immune cells to contact invading parasites, and they respond by sending specific or generic signals that polarize T cell responses [97,98]. DCs can be divided into CD11c+ myeloid DCs (mDCs) and CD123+ plasmacytoid DCs (pDCs) [99], both of which are immature DCs with distinct roles. MDCs are believed to preferentially induce T cell responses to invading pathogens while pDCs are presumed to contribute to innate antiviral responses and self-antigen tolerance [100,101]. Since DCs are the first to encounter the parasite Sh in all its forms, including eggs that migrate into tissue, it has been hypothesized that they may play a part in the known T cell hyporesponsiveness occurring in chronic Sh infections [102].
Two studies have reported that individuals with Sh infection had lower mDCs [102,103] and pDCs [102] than individuals without Sh infection. In adults in Gabon, both mDCs and pDCs had lower HLA-DR expression in blood [102], while in children and adults in Zimbabwe no differences were seen in activation marker expression (HLA-DR or CD86) [103]. Interestingly, when the Zimbabwean analysis was restricted only to children aged 5–10 years, those with Sh infection had more mDCs and lower levels of HLA-DR expression than children without Sh infection [103]. On further analysis, both pDCs and mDCs from the Gabonese adults with Sh infection had reduced capacity to respond to toll-like-receptor (TLR) ligands with decreased effector marker expression (CD40, CD80, HLA-DR, and CCR7) compared to adults without Sh infection, which was more pronounced in mDCs with decreased cytokine production (IL-6, IL-12, TNF-α, IL-10) and mitogen-activated protein kinase signaling [102]. Co-culture of mDCs isolated from these adults with Sh infection with naïve T cells led to lower production of IL-4 and IFN-γ and expression of the activation marker CD25, emphasizing a potential role of DCs functional impairment in mediating T cell hyporesponsiveness in chronic Sh infection [102].
Overall, there appears to be an age-related pattern in DCs immune response to Sh infection which may reflect the chronicity of the infection, with lower levels of mDCs particularly in adults with Sh infection. These lower circulating mDCs levels might correlate with impaired mDCs response in chronic Sh infection, and/or could represent increased recruitment of this cell population to the target sites of Sh infection. Such a decrease in systemic mDCs in blood could have further implications such as an impairment of immune response against concurrent bacterial or viral infections, for which the host immune response which relies on antigen presenting cells to induce pertinent T cell responses [104].
Monocytes
Monocytes are circulating white blood cells with phagocytotic capabilities. They can differentiate into macrophages or dendritic cells after migration from blood into tissue, and can express the activation marker, CD16 [105], linking humoral and innate cellular immune responses [106]. Three studies in total have examined circulating monocytes in Sh infection.
In South African women with Sh infection, circulating monocytes were increased and had higher expression of the HIV entry molecule CCR5, compared to women without Sh infection. However, no difference was observed in monocyte CCR5 expression in cells collected from the cervix in the same women [107].
In two other studies, no difference was seen in circulating monocytes between individuals with Sh infection and participants without Sh infection [62,108], but one reported lower CD16 expression in systemic monocytes of participants with Sh infection aged 16 and above from Zimbabwe [108]. This lower CD16 expression could lead to weaker innate immune responses in those with Sh infection. Further, healthy participants without Sh infection had a positive correlation between CD16 monocyte expression and IgG and IgG1 levels against schistosome antigen SEA and WWH, which has been associated with resistance to infection [109,110].
The disparity in monocyte findings of the above studies could be attributed to variations in sex distributions among the two study populations. The study in Zimbabwe consisted of both sexes (60% females) with a mean age 16.4 years, while all 44 female participants were above 14 years of age in the South African study. Given evidence of sex-dependent immune responses to schistosome infection [83], these differences in study populations could explain the higher monocyte levels seen in the Kleppa study.
Granulocytes
Eosinophils have been well established to play a critical effector cell role in the immune response against helminth infections and are a cardinal sign of parasitic infection [111]. In S. mansoni infections, eosinophils can kill cercariae and adult worms in a degranulation- and IgE-dependent manner [112]. Five studies examined eosinophils in Sh infection.
People with Sh infection in Senegal who had sonographic genitourinary pathology exhibited higher eosinophil and granulocyte levels compared to individuals with Sh infection without pathology and/or people without Sh infection [113]. This might indicate the heightened immune responses in the presence of ongoing Sh-mediated genitourinary pathology, implying a pathogenic role of eosinophils in chronic inflammation and tissue damage. No differences were reported in neutrophils between Senegalese adults with and without Sh infection and children in this study [113] nor in Zimbabwean pre-school aged children [66].
The effect of PZQ treatment on eosinophil counts is inconclusive. One study reported no change 9 weeks post-treatment in 47 Malian children and adults [84] while another study by the same group showed increased eosinophils 9 weeks post-treatment in 326 Malian children and adults [85]. Higher eosinophil counts post-treatment were positively associated with reinfection 2 years after treatment [85]. In contrast, a study from The Gambia reported that children with prior Sh infection who remained uninfected one year after PZQ treatment had higher circulating eosinophils than children who became reinfected [114]. Of note, the study in Mali did not report eosinophil counts at the 2-year follow up, and hence used the preceding eosinophilia as a predictive factor for reinfection. In contrast, the study in The Gambia reported the association between Sh reinfection and low eosinophil count at 12 months after PZQ-treatment and therefore assessed the association of low eosinophils and Sh infection at the same time point.
Innate lymphoid cells
Innate lymphoid cells (ILC) are a newly discovered immune population that mainly reside at mucosal sites and play a critical role in mucosal immunology. ILCs can be categorized into three distinct groups that mirror the Th1, Th2, and Th17 cell subsets. ILC1, mirroring Th1, produce IFN-γ upon activation to promote host defense against pathogens, particularly of viral and bacterial origin. ILC3s, similar to Th17 cells, promote tissue repair, contain commensal bacteria, and protect against pathogenic bacteria [115,116].
Similar to Th2 cells, ILC2s are elicited during parasitic infections and regulate tissue immunity and inflammation by producing Th2 cytokines (IL-4, IL-5- and IL-13) to recruit and activate eosinophils and alternatively activated macrophages. In this way, ILC2s mediate anti-helminth immunity and can also be associated with allergic reactions with increased presence in bronchial secretions of asthmatic patients [116].
Thus far only Nausch et al [117] have investigated the impact of Sh infection on ILCs. People with Sh infection had lower circulating ILC2 frequencies versus people without Sh infection, a difference that was most profound in the youngest aged 6–9 years. ILC2 frequencies also negatively correlated with infection intensity assessed by urinary egg burden. Upon re-evaluation of 12 of the 36 previously participants with Sh infection 6 weeks after PZQ therapy, ILC2 frequencies had increased to frequencies comparable to those reported in participants without Sh infection. Th2 cytokines (IL-4, IL-5 and IL-13) were only associated with infection intensity in the oldest age group aged 14–18 years of age [117]. This observed decrease in systemic ILC2 in individuals with Sh infection may be due to increased migration to affected tissues, initiating a local immune response leading to fewer ILC2s detectable in blood. Conclusions about the effects of PZQ are limited by the follow-up to one third of individuals who were initially infected.
Systemic adaptive immunity
In total, 25 studies have assessed changes in adaptive immune cells seen in Sh infections (Tables 5–7).
Table 5. S. haematobium infection and host systemic lymphocytic proliferation in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| Feldmeier et al 1981 (118) | Sudan, Germany (different African immigrants from Sh endemic countries) | 45 | Not documented | 6–44 | In response to antigen stimulation (PHA, PWM, CON-A, PPD, Sm-antigen): = Lymphocyte proliferation |
N/A | Sh infection had no impact on lymphocyte proliferation to various antigen stimuli. |
| Grogan et al 1998 (68) | Gabon | 12 | F (58%) | Median 11 | IL-10 blockade: ↑ Lymphocyte proliferation (with and without AWA stimulation) |
N/A | IL-10 blockade augmented lymphocyte proliferation in individuals with Sh infection. |
| Grogan et al 1998 (75) | Gabon | 47 | N/A | Children- adults |
Sh-reinfected vs uninfected s/p PZQ 2 years prior: ↓ Lymphocyte proliferation (with AWA stimulation only) |
N/A | Individuals with prior Sh infection who became reinfected had decreased lymphocyte proliferation in response to Sh antigens. |
| Mduluza et al 2001 (57) | Zimbabwe | 4 | Not documented | 10–12 | = Lymphocyte proliferation to PHA, SEA and SWAP | N/A | Lymphocyte proliferation remained unchanged in individuals with Sh infection to various antigen stimuli. |
| Mduluza at al 2003 (88) | Zimbabwe | 40 | Not documented | 7–16 | In high endemic area: ↓ Lymphocyte proliferation to SEA = Lymphocyte proliferation to PHA In low endemic area: ↑ Lymphocyte proliferation to SEA = Lymphocyte proliferation to PHA |
In high endemic area: = Lymphocyte proliferation to SEA and PHA In low endemic area: = Lymphocyte proliferation to SEA and PHA |
Response to SEA in individuals with Sh infection varied among different areas depending on Sh endemicity. There was no change in lymphocyte proliferation after PZQ treatment. |
| Schmiedel et al 2015 (119) | Gabon | 38 | F (89%) | mean 10 | N/A | = Lymphocyte proliferation pre- and post-PZQ treatment 6 weeks after treatment |
Sh infection had no impact on lymphocyte proliferation prior and after PZQ therapy. |
Sh = S. haematobium, Sm = S. mansoni, PHA = Phytohemagglutinin, PWM = pokeweed mitogen, PPD = purified protein derivate, AWA = adult worm antigen; SEA = schistosomal egg antigen, SWAP = soluble antigen preparation of adult schistosomes
Table 7. S. haematobium infection and host B cell immune response in the systemic circulation in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| *Labuda et al 2013 (139) | Gabon | 56 | 43% F | 8–16 | ↑ MBC ↑ CD23 expression on B cells (after BCR stimulation) ↓ Ki-67+ B cells, and naïve B cells ↓ MBC proliferation (after BCR stimulation) ↓ TNF-α MBCs (after BCR stimulation) |
↑ Naïve B cells ↓ MBC (exception: TNF-α producing MBCs) ↑ B cell responsiveness restored 6 months after at least 3 rounds of treatment |
Sh infection led to an increase of MBC and B cell subsets which was at least partially resorted 6 months after PZQ treatment. |
| *Lyke et al 2012 (138) | Mali | 84 | 51% F | 4–14 | ↑ MBC (after SEA and SWAP stimulation) | N/A | Stimulation with Sh antigen led to an increase in MBC proportions in individuals with Sh infection. |
| Rujeni et al 2013 (140) | Zimbabwe | 434 | 60% F | mean 8.2–39 |
↑ Soluble CD23 with infection intensity | N/A | Soluble CD23 increased with infection intensity. |
| *Van der Kleij et al 2004 (62) | Gabon | 25 | F (40%) | 8–15 | = Monocytes, B cells, T cells | N/A | Sh infection did not impact systemic T cell, B cell or monocyte frequencies. |
| *van der Vlugt et al 2012 (141) | Gabon | 20 | 55% F | 8–14 | ↑ Breg subpopulation (CD1dhi B cells) BCR stimulation: ↑ IL-10 production by B cells |
BCR stimulation: ↓ IL-10 production by B cells 6 months after at least 3 rounds of treatment |
Sh infection led to an expansion of a Breg subpopulation (CD1dhi B cells) and increase in IL-10 production by B cells. IL-10 production decreased in B cells post-PZQ. |
| *van der Vlugt et al 2014 (142) | Gabon | 42 | 50% F | 16–28 | After stimulation with generic antigens: ↑ Breg subpopulations: CD1dhi B cells IL-10+ B cells IL-10+ CD1dhi B cells CD24hiCD27+ B cells LAB+ B cells Co-culture of healthy CD4+ T cells with CD1dhi B cells of individuals with Sh infection subjects: ↓ IFN-γ production by CD4+ T cells ↓ IL-4 production by CD4+ T cells ↓ Il-17 production by CD4+ T cells ↑ IL-10+ T cells ↑ Tregs → Depletion of CD1dhi B cells decreased IL-10+ T cells production of CD4+ T cells |
N/A | Sh infection led to an expansion of Breg subpopulations which supressed CD4+ T cell function in vitro and increased regulatory T cell popualtions (Tregs and IL-10+ T cells). |
Sh = S. haematobium, MBC = memory B cells, Bregs = B regulatory cells BCR = B cell receptor, PZQ = Praziquantel, SEA = Soluble egg antigen, SWAP = Soluble worm antigen
*Studies included participants with additional parasitic infections.
Table 6. S. haematobium infection and host T cell immune response in the systemic circulation in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| Appleby et al 2015 (136) | South Africa | 94 | F (56%) | 5–54 | In response to SWAP ↓ CD3ζ expression on T cells associated with increased Sh intensity ↑ CD3ζ expression associated with PBMC Proliferation |
N/A | CD3ζ downregulation was associated with increased Sh infection intensity without limiting proliferative capacity of PBMCs in response to Sh antigen. |
| Caserta et al 2012 (134) | Zimbabwe | 105 | Not documented | 6–16 | ↑ CD200R+ CD4+ T cells (baseline and with infection intensity) | N/A | Inhibitory receptor CD200R epxression was increased in individuals with Sh infection and increased with infectious burden. |
|
*DiNardo et al 2018 (128) |
Swaziland | 38 | F (59%) | 6 mo– 15 years | In response to ESAT-6 and CFP-10 to elicit an MTB specific immune response: ↓ Th1:Th2 ratio ↑ IL-4 producing CD4+ T cells ↓ TNF-α and IFN-γ producing CD4+ T cells |
In response to ESAT-6 and CFP-10 to elicit an MTB specific immune response: ↑ Th1:Th2 ratio ↓ IL-4 producing CD4+ T cells ↑ TNF-α and IFN-γ+ producing CD4+ T cells 6 months after treatment |
Individuals with Sh infection had decreased MTB specific Th1 CD4+ T cell function, with associated increases in Th2 cells. |
| Grogan et al 1996 (112) | Gabon | 110 | Male and female (%, not documented) | 5–48 | ↓ T cell proliferation to AWA ↓ IL-4 to AWA and SEA = IL-5 and IFN-γ |
↑ T cell proliferation to AWA ↑ IL-4 to AWA and SEA = IL-5 and IFN-γ 5 weeks after treatment |
Sh infection led to low antigen specific T cell proliferation and lL-4 production. |
| Kleppa et al 2014 (107) | South Africa | 44 | F (100%) | 15–23 | Women with FGS vs without FGS (defined by visualization of sandy patches): = CD4+ T cells ↑ Monocytes (CD14+) ↑ CCR5+ CD4+ T cells ↑ CCR5+ Monocytes (CD14+) |
Women with FGS vs without FGS: ↓ CCR5+ CD4+ T cells ↓ CCR5+ Monocytes (CD14+) 7–8 months after treatment |
HIV entry molecule CCR5 was increased on systemic CD4+ T cells and monocytes in women with sandy patches, and decreased post-PZQ. |
| Kleppa et al 2015 (124) | South Africa | 765 | F (100%) | mean 18.9 | = CD4+ T cells | N/A | Sh infection did not impact CD4+ T cell counts. |
| Kroidl et al 2019 (125) | Tanzania | 235 | F (42%) | 18–62 | = HLA-DR+ T cell | N/A | There were no differences in HLA-DR+ T cell frequencies. |
| *Labuda et al 2020 (58) | Gabon | 79 | Male and female (%, not documented) | School-children | In response to AWA and SEA = CD4+ TCM cells, CD4+ T EMRA cells, and CD4+ TEM cells ↑ IFN-γ, IL-2, IL-5, IL-10, and TNF-α to AWA, SEA = IFN-γ, IL-2, IL-5, IL-10, and TNF-α to PHA ↑ Tregs |
In response to AWA and SEA = CD4+ TCM cells and CD4+ T EMRA cells ↑ TEM cells ↑ IFN-γ, IL-2, IL-5, IL-10, and TNF-α to AWA, SEA ↑ IL-10 to PHA 7 months after treatment ↓ Tregs 6 weeks and 7 months after treatment |
Tregs were increased in individuals with Sh infection. PZQ treatment led to decreased Tregs, increased effector T-cells and antigen-specific cytokine production in previously infected. There was no difference in systemic effector CD4+ T cell populations, but TEM cells increased after PZQ treatment. |
| Mbow et al 2013 (113) | Senegal | 26 | F (50%) | 5–14 | ↑ Th17 cells (with GU pathology) ↑ IL-17 producing CD4+ T cells ↑ Ratio: Th17 to Tregs (with GU pathology) ↑ Ratio: IL17+ to IL-10+ CD4+ T cells (with GU pathology) = Tregs (CD4+CD25highFoxp3+ and CD4+Foxp3+) = IL-10+CD4+ T cells = CD4+T-bet+ = CD4+IFN-γ+ = CD4+GATA3+ = CD4+IL-4+ T cells |
N/A | Immune dysregulation was more pronounced in individuals with Sh infection with GU pathology comapred to without. Tregs tended to be lower in individuals with Sh infection with GU pathology and the same group had a higher ratio of Th17 cells to Tregs primarily due to the presence of elevated Th17 cells. |
| Nausch et al 2011 (117) | Zimbabwe | 49 | Male and female (%, not documented) | 8–60 | = CD25+Foxp3- CD4+ T cells ↑ Tregs (with infection intensity) in < 14yo ↓ Tregs (with infection intensity) in > 14yo |
N/A | There were no differences in activated CD4+ T cells. In individuals with Sh infection < 14 years of age, Tregs positively correlated with infection intensity, while there was a negative correlation in >14 years of age. |
| Nausch et al 2012 (103) | Zimbabwe | 105 | F (57%) | 6–84 | ↓ CD4+ memory T cells and CD4+ TEM cells ↓ CTLA-4+ CD4+ T cells = CD4+ and CD8+ T cells = CD4+ TCM cells = CD8+ memory T cells = CD31+CD4+ T cells = IL-4 after WWH stimulus ↓ IFN-γ after WWH stimulus No association between CD4+ memory T cells and IFN-γ or HLA-DR CD4+ T cells after PHA stimulation |
↓ CD4+ T cells and CD4+ T memory cells = CD31+CD4+ T cells (trend) ↑ CD31+CD4+ T cell proliferation (indicated by shortened telomerase lengths) 6 weeks after treatment |
Individuals with Sh infection had decreased CD4+ memory, EM and CTLA-4+ T cells as well as lower IFN-γ levels after Sh antigen stimulus. CD4+ memory and EM T cells remained low 6 weeks after PZQ therapy, although CD31+ CD4+ (naïve) memory T cell proliferation increased after treatment in previous individuals with Sh infection. |
| Nmorsi et al 2005 (123) | Nigeria | 250 | Male and female (%, not documented) | 5–60 | ↓ CD4 ↑ CD8 ↓ CD4:CD8 ratio ↑ CD4:CD8 ration with infection intensity |
N/A | Individuals with Sh infection had lower CD4+ T cells and CD4:CD8 T cell ratio compared to uninfected. CD4:CD8 T cell ratio increased with Sh infection intensity. |
| Schmiedel et al 2015 (119) | Gabon | 38 | F (89%) | mean 10 | ↑ Tregs ↓ Th1 and Th2 cytokines to AWA, SEA and BCG = PBMC proliferation |
↓ Tregs ↑ Th1 and Th2 cytokines to AWA, SEA and BCG = PBMC proliferation 6 weeks after treatment |
Tregs were upregulated in individuals with Sh infection and were associated with lower Th1 and Th2 cytokine production, which reversed post-PZQ. |
| Van der Kleij et al 2004 (62) | Gabon | 25 | F (40%) | 8–15 | = Monocytes, B cells, and T cells | N/A | Sh did not impact systemic T cell, B cell or monocyte frequencies. |
Sh = S. haematobium, SWAP = Soluble worm antigen preparation, CM = central memory, EM = effector memory, EMRA = terminally differentiated effector memory T cells, MTB = Mycobacterium tuberculosis, mo = months, PHA = Phytohemagglutinin, BCG: bacille Calmette-Guerin, yo = year old; WWH = whole worm homogenate
*Studies included participants with additional parasitic infections.
S. haematobium infection and host systemic lymphocytic proliferation in humans
In three studies, lymphocyte proliferation was similar among individuals with Sh infection and without Sh infection in response to stimulation by generic antigens [57,88,118] and by schistosome antigens AWA and SEA before and after PZQ chemotherapy [119]. In contrast, in a Gabonese cohort, lymphocyte proliferation was reduced after schistosome antigen stimulation with AWA but not egg antigen SEA [75] in peripheral blood from those with versus without Sh infection. Further, a cohort study in Zimbabwe showed changes in lymphocyte proliferation in individuals with Sh infection depending on Sh endemicity levels in their area of residence. Those living in a low-endemic Sh area had higher lymphocyte proliferation in comparison to those without Sh infection from the same area, while the opposite was seen in participants living in a Sh high-endemic area. These proliferative responses did not change in either population 12 and 18 months after PZQ treatment and no difference was seen in response to generic antigen stimulation with PHA [88]. This study reflects the complexity of assessing immune responses from different populations living in different environments and again highlights the multiple factors that evidently influence an individual’s immune response to Sh infection. These factors may include the individual’s exposure history beyond parasitic infections which can impact their immune status and memory, as well as overall health, microbiome, sex, and age.
S. haematobium infection and host T cell immune response in the systemic circulation in humans
T cells play a crucial role in the immune response against invading pathogens, including schistosome infections [28]. Both CD4+ and CD8+ T cells are critical in protecting the host against pathogens, with CD8+ T cells being particularly important in fighting intracellular pathogens including viruses and bacteria, as well as in eliminating malignant cells in cancer [120].
Some effector CD4+ and CD8+ T cells will develop into memory T-cells, which after antigen encounter can rapidly expand upon re-encountering the pathogen. Memory T cells can be further subdivided into multiple subpopulations including central memory and effector memory T cells [121]. Central memory T cells reside mainly in lymphoid tissue and blood, while effector memory T cells are present in blood and traffic through peripheral organs [122].
CD4+ T cells have a wide array of functions that rely on specialization through functional polarization. CD4+ T cell subsets addressed in manuscripts included in this review include Th1, Th2, Th17 and Tregs. The characteristic immune alteration induced by helminth infections is an increase in Th2 cells and a decrease in Th1 cells [33]. Th17 cells provide protection and immunity against extracellular pathogens, especially at mucosal tissue, and play a role in the pathogenesis of multiple chronic inflammatory diseases [52]. Tregs, characterized by high expression of IL-2 receptor α chain, CD25, and Foxp3+, are important in the maintenance of peripheral immune tolerance [36]. Each of these subsets will be discussed in detail in this section.
CD4+ and CD8+ T cells
Overall frequencies of T cells largely do not appear to differ between individuals with and without Sh infection [62], though multiple studies have reported altered composition of T cell subsets. Analysis of T cell subsets in people with Sh infection compared to individuals without infection showed lower CD4+ (257 versus 681) and higher CD8+ (210 versus 114) T cells/μL in a Nigerian cohort without HIV infection [123]. Notably, no information was given on where the 44 negative control subjects were recruited from, which might shed light on the major differences in CD4+ T cell numbers between the groups. Further, decreased CD4+ to CD8+ T cell ratios were associated with heavy Sh infection in children and adults (urine eggs >50/mL) compared to ratios in those with light infections. The authors reported that lowest ratios were found in infected adults, followed by children with Sh infection, as compared to the control group without infection, demonstrating an age dependent pattern in host immune response to Sh [123]. Contrastingly, Nausch et al [103] did not find a difference in circulating CD4+ or CD8+ T cell frequencies in persons with or without Sh infection in their HIV-uninfected Zimbabwean study population which at least is partially attributable to lower infection intensity in comparison to the Nigerian cohort. A South African study also did not find a difference in mean CD4 cell count in women with or without Sh infection or clinical evidence of FGS, regardless of HIV status [124].
In a cohort of 235 men and women who did not have HIV infection in Tanzania, 82.1% were helminth infected and only 9.3% were individuals with Sh infection [125]. No difference was seen in HLA-DR+ T cell frequencies comparing individuals without Sh infection, which included participants with and without other helminth infections, to individuals with Sh infection. Notably, the small number of individuals with Sh infection in this cohort warrants caution when interpreting these results.
Memory T cells
Observed associations of Sh infection with CD4+ and CD8+ T cell memory subsets vary. In Gabonese schoolchildren, the frequency of CD4+ effector memory T cells increased in children with Sh infection post-PZQ treatment, but there was no difference at baseline between CD4+ effector or memory T cells [58]. In contrast, Nausch et al found that children and adults with Sh infection at baseline had lower CD4+ memory and effector memory T cells than uninfected [126]. Stimulation of CD4+ memory T cells with generic antigen led to increased activation, assessed by HLA-DR+ expression, and increased IFN-γ secretion in individuals without but not in individuals with Sh infection, highlighting possible functional impairment of CD4+ memory T cells in the setting of Sh infection. Neither group produced Th2 cytokines (IL-4, IL-5) in response to stimulation [126]. In the same study, PZQ treatment of those with Sh infection led to decreased CD4+ T cells and CD4+ memory T cells, increased proliferation of naïve thymic CD31+CD4+ T cells, and no changes in CD8+ T cell and CD8+ memory T cell frequencies at 6 weeks [126]. From these studies together, it appears that CD4+ memory T cells are an important source of IFN-γ production that are lower in persons with Sh infection and may further decrease at 6 weeks after treatment [126]. Follow-up beyond 6 weeks was not performed, rendering longer-term effects of PZQ on CD4+ memory T cells unknown.
Th1 and Th2 cells
Two studies examined Th1 and Th2 CD4+ T cell populations in Sh infection. PBMCs in response to stimulation with AWA or SEA of individuals with Sh infection in Gabon had lower T cell proliferation and lower IL-4 production, both of which were reversed after PZQ treatment [127]. Notably, IL-4 production was abolished by CD4+ T cell depletion, but not by CD8+ T cell depletion [127].
Further supporting these findings, PBMCs of children with Sh infection from Swaziland stimulated with Mycobacterium tuberculosis (MTB) antigens developed a lower Th1:Th2 cytokine ratio, determined by the ratio of IFN-γ and TNF-α to IL-4, than children without Sh infection, and their CD4+ T cells produced greater MTB specific IL-4, with a decrease in MTB specific IFN-γ and TNF-α [128]. Six months after chemotherapy, the Th1:Th2 ratio increased and MTB specific IFN-γ and TNF-α producing CD4+ T cells were detected, but all of these remained lower than in children without Sh infection [128]. Overall, this study suggested an Sh-associated decrease in MTB specific Th1 CD4+ T cell function, with associated increases in Th2 cells, raising concern for a compromised immune response to MTB in individuals with Sh infection which may not be entirely reversed after treatment.
Th17 cells
Only one study to date reported on Th17 cells in the setting of Sh infection. In Senegalese children, Th17 cells (CD3+CD4+RORγt+) were elevated in individuals with Sh infection with sonographic evidence of genitourinary pathology than individuals with Sh infection without pathology and matched individuals without Sh infection [113]. Although IL-17 producing CD4+ T cells tended to be higher overall in individuals with versus without Sh infection, the greatest differences was noted between individuals with Sh infection with genitourinary pathology compared to those with Sh infection but without pathology [113]. Investigators also reported that both individuals with and without Sh infection with genitourinary pathology had higher ratios of IL17+ to IL-10+ CD4+ T cells compared to those individuals with Sh infection without genitourinary pathology. These cytokine findings accord with their finding that participants with pathology had a higher ratio of Th17 cells to Tregs, primarily due to the presence of higher levels of Th17 cells [113]. Though a single study, this work importantly highlights the potential role of Th17 cells in Sh-induced tissue pathology, a role that has been suggested in S. mansoni and S. japonicum infection as well [129–131].
T regulatory cells
A total of 4 studies investigated Treg populations in Sh infection. Most studies (3 out of 4) demonstrated an increase in systemic Tregs individuals with Sh infection compared to uninfected [58,119,132], and both studies that assessed the effect of PZQ treatment reported that Tregs decreased after anti-helminthic treatment [58,119].
Mbow et al, described above, found no differences in Tregs between those with Sh and genitourinary pathology, Sh without pathology, and without Sh infection [113].
In addition to finding that Tregs normalized after PZQ treatment in Gabonese children infected with Sh, Schmiedel and colleagues also reported that both Th1 (IL-17, IFN-γ, TNF) and Th2 (IL-5, -10, -13) cytokine responses to schistosome and MTB antigen stimulation increased post-treatment [119]. Furthermore, ex vivo depletion of Tregs led to an increase in both Th1 and Th2 cytokine responses to both schistosome and MTB antigen stimulations in samples of individuals with Sh infection before treatment and after treatment. This demonstrates the persistent suppressive capacity of Tregs, even following a decrease in their numbers post-PZQ [119].
Of note, Nausch et al found that Tregs increased with infection intensity in those below 14 years of age, but the opposite was seen in individuals above age 14 with decreasing Tregs in those with higher Sh burden [132]. Overall children with Sh infection (< 14 years of age) had higher Treg proportions than children without infection, while Treg proportions were lower in the people with versus without infection older than 14 years. Notably, in these older patients, the burden of Sh was lower, possibly reflecting the development of acquired anti-schistosome immunity with age that could contribute to a diminished regulatory response [132].
Together, these studies suggest that Tregs play a major and potentially age-dependent role in the immune response to Sh infection. During youth, when individuals have less acquired immunity, higher Treg proportions may be crucial in dampening excessive inflammation and downstream pathology. As host protective acquired immunity develops with age, the necessity for an enhanced regulatory phenotype that was seen in children may decrease.
T cell marker expression
A total of four studies examined T cell surface markers in Sh infection. CD4+ T cells that expressed the inhibitory protein Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) were decreased in individuals with Sh infection compared to persons without infection. Notably, CTLA-4+CD4+ T cells increased with age in those individuals with Sh infection but did not change with age in those without Sh infection [126].
In a study in Zimbabwe, expression of the regulatory molecule CD200 receptor (CD200R) [133], was higher on CD4+ T cells of persons with Sh infection. Further, CD200R-expressing cells appeared to belong predominantly to the Th2 lineage, with IL-4 secreting CD4+ T cells almost all expressing CD200R while IFN-γ secreting CD4+ T cells expressed significantly less CD200R [134]. CD200R expression on CD4+ T cells also correlated positively with infection intensity [134]. These studies indicating increased expression of immune regulatory proteins CTLA-4 and CD200R suggest a state of immune suppression, potentially influencing the effectiveness of the immune response to other pathogens, particularly viral.
A study in South Africa reported a negative correlation between CD3ζ expression on T cells, which promotes downstream immune responses including cell proliferation [135], and infection intensity, while noting a positive correlation between CD3ζ expression and PBMC proliferation in response to schistosome antigen stimulation with SWAP [136]. The authors hypothesized that CD3ζ downregulation could be a mechanism for immune dysregulation that is observed during chronic Sh infection in humans without changes in the absolute numbers of T cells. It is thought that immune dysregulation in addition to local mucosal damage may contribute to the increased risk of HIV acquisition seen in some studies of women with Sh infection [8,12,137]. In accordance with this, women with FGS (defined as presence of sandy patches on colposcopy exam) were found to have increased expression of the HIV entry molecule CCR5 on both systemic circulating and local cervical CD4+ T cells and CD14+ monocytes, which decreased on both cell populations post-PZQ treatment in both compartments [107].
Overall synthesis of T cell studies in Sh infection
Together, these 14 studies indicate that systemic T cells play a crucial role in immunity against Sh infections. It appears that Sh infection leads to increases in T cell populations which augment suppressive and regenerative functions on the immune system, particularly upregulating Th2 immune responses, Tregs, and Th17 cells. These increases appear to be accompanied by decreases in CD4+ memory and effector, Th1, and IFN-γ producing T cell populations. These systemic immune changes may further explain why individuals with Sh infection may be more susceptible to a variety of different pathogens [29].
S. haematobium infection and host B cell immune response in the systemic circulation in humans
In contrast to the abundance of data examining T cells in Sh infection, only 6 studies have investigated B cells. One study showed no difference in B cell frequencies between individuals with and without Sh infection [62]. Two others reported that activated B cells, memory B cells, and Bregs are higher during Sh infection. Sh infection has been associated with an increase in memory B cells in response to schistosome antigens SWAP and SEA in a Malian cohort [138] and at baseline in a Gabonese cohort [139] compared to the uninfected individuals in each cohort. At a functional level, B cells were shown to have increased expression of the activation marker CD23, similar to the rising soluble CD23 levels with Sh infection intensity described by Rujeni et al [140]. B cells from children with Sh infection further had lower proliferation and intracellular B cell TNF-α production compared to children without Sh infection [139]. Notably, PZQ treatment led to an increase in naive B cells, decrease in memory B cells apart from TNF-α producing memory B cells, and restoration of B cell responsiveness [139].
In a different study in Gabon, children with Sh infection had elevated CD1dhi B cells, a Breg subpopulation, compared to children without Sh infection, with elevated IL-10 production by B cells after stimulation, which was reduced post-PZQ treatment [141]. Stimulation of B cells with antigens PMA, ionomycin, brefeldin A (PIB) and LPS from individuals with Sh infection led to induction of multiple different Breg subpopulations compared to individuals without Sh infection. Co-culture of CD1hi Bregs from persons with Sh infection together with CD4+ T cells led to a decrease in IFN-γ, IL-4 and IL-17 production by CD4+ T cells, and increased frequencies of Tregs and IL-10+ T cells [142]. Depletion of CD1hi Bregs in the CD4+ T cell co-culture restored IL-10+ T cell numbers, while Tregs remained the same [142].
Together, these data suggest that Sh infection induces changes in the B cell compartment including an increase in Bregs, which may play a key role in inducing T cell hyporesponsiveness and altering memory B cell subsets. Bregs have been shown to suppress Th1 immune response [143] and suppress viral specific CD8+ T cell responses in individuals with HIV, hepatitis B, and hepatitis C [144,145]. Increases in Bregs and alterations in memory B cells subsets might offer at least one mechanism by which Sh infection is associated with increased acquisition of certain viral infections and worse outcomes in individuals with Sh and viral co-infections.
S. haematobium infection and the host local genitourinary tissue immune response in humans
Six studies have examined local mucosal immune responses in Sh infection in humans (Table 8).
Table 8. S. haematobium infection and the local tissue host immune response in humans.
| Study | Country | Sample size | Sex (female in %) | Age in years | Compartment | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Overall conclusion |
|---|---|---|---|---|---|---|---|
| Dupnik et al 2019 (149) | Tanzania | 57 | F (100%) | 20–35 | Genital compartment (CVL) | ↓ IL-15 | Women with Sh infection had lower IL-15 concentrations in CVL samples. |
| Jourdan et al 2011 (156) | Malawi | 61 | F (100%) | 15–45 | Genital compartment (cervical tissue biopsies) | Women with Sh ova in cervical biopsies vs no ova (Malawian and Norwegian controls): ↑ CD4+ T cells = Langerhans cells and CD8+ T cells Women with Sh ova in cervical biopsies with viable ova vs calcified ova: ↑ CD68+ macrophages in tissue with viable ova vs calcified ova |
Sh ova in cervical tissue were associated with a higher CD4+ T cell response. Only viable Sh ova in cervical tissue, not calcified ova, led to an influx of CD68+ macrophages. |
| Kleppa et al 2014 (107) | South Africa | 44 | F (100%) | 15–23 | Genital compartment (Cytobrush samples) | Women with versus without genital sandy patches: = Monocytes (CD3-D56-CD14+) = CCR5+ Monocytes = CD4+ T cells = CCR5+CD4+ T cells Praziquantel treatment of Sh infection led to: ↓ CCR5+ Monocytes ↓ CCR5+ CD4+ T cells |
Women with sandy patches did not have altered cervical CCR5 expression on monocytes or CD4+ T cells, but expression decreased after PZQ treatment. |
| Leutscher et al 2005 (157) | Madagascar | 240 | F (0%) | 15–49 | Genital compartment (Seminal) | ↑ Leukocytospermia Moderate to high egg burden vs uninfected: ↑ Eosinophils ↑ IL-10 |
Men with Sh infection had increased leukocytospermia. Other seminal changes including increased eosinophils and IL-10 were only observed in men with high seminal Sh egg burden. |
| Njaanake et al 2014 (67) | Kenya | 158 | F (55%) | 5–12 | Genitourinary compartment (Urine) | High intensity Sh infection vs low infection intensity: ↑ IL-6 ↓ IL-10 Individuals with Sh infection with urinary tract pathology seen on US versus no pathology seen: ↑ IL-6 ↓ TNF-α Hematuria associated with: ↑ IL-6 ↓ IL-10 |
Elevation of pro-inflammatory cytokine IL-6 and lower levels of Th-2 associated cytokine IL-10 were associated with Sh egg burden and GU pathology in Sh infected children. |
| Sturt et al 2021 (148) | Zambia | 212 | F (100%) | 18–31 | Genital compartment (CVL) | Women with FGS vs without FGS: ↑ IL-5 = IL-1β, IL-6, IFN-γ, IL-8, MIP-1 α /b, MCP-1, IP-10, and eotaxin Women with FGS and probable FGS vs FGS uninfected: ↑ TNF-α High FGS burden vs without FGS: ↑ IL-4, IL-5, IL-13, IL-1α, and IL-15 Elevated Sh DNA genital concentration vs without FGS: ↑ IL-4, IL-5, IL-13, IL-1, IL-15, and TNF-α |
FGS altered the local cervical mucosal immune environment, increasing Th2 associated and inflammatory cytokines. |
Sh = S. haematobium, FGS = Female genital schistosomiasis, CVL = cervical vaginal lavage, US = ultrasound
Schistosome eggs are highly immunogenic and cause a strong local immune response [94]. Eggs migrating through tissue can become entrapped in organs of the genitourinary system, including not only the bladder but also reproductive organs, causing female and male genital schistosomiasis (FGS, MGS) [35,146] with symptoms dependent on egg location [147]. In MGS eggs become entrapped in male genital organs including seminal vesicles, prostate gland, and vas deferens causing local inflammatory responses with subsequent tissue damage and scarring [146]. Similarly, in FGS eggs become entrapped in female reproductive organs, including the cervix and vagina, leading to tissue damage which can cause a wide array of symptoms including discharge, pain, and infertility [35].
A recent study in Zambia by Sturt et al [148] evaluated cervical immune changes in women with definite FGS (positive vaginal or cervical Sh PCR), probable FGS (urinary Sh eggs or CAA with one of four typical cervical findings), and those without FGS (absence of these findings) [148]. In the primary analysis, cervical lavage (CVL) specimens of women with definite FGS demonstrated elevated IL-5 compared to women without FGS, without differences in other genital cytokines. In exploratory analyses, women with high Sh FGS burden, defined as two or more positive genital Sh PCRs, had higher concentrations of Th2 cytokines IL-4, IL-5, and IL-13 as well as inflammatory cytokines IL-1 α and IL-15 compared to women without FGS [148]. In a second exploratory analysis, after adjustment for multiple comparisons, cervical Th2 cytokines IL-5 and pro-inflammatory cytokine TNF-α were associated with FGS. Of note, a study in Tanzania found decreased IL-15 levels in CVL samples of women infected with Sh as diagnosed by presence of elevated CAA plus Sh eggs in urine, but no difference in any of the other 26 measured cytokines [149].
The diverse results of local cervical cytokine expressions might reflect the different study designs among women with Sh infection. While the Tanzania study evaluated cervical cytokines in all women with Sh infection (therefore possibly including some women who had parasitic infection but without genital tract involvement), the Zambia study’s strict requirement of PCR-confirmed Sh infection in the genital tract likely restricted that study population to a younger age group and/or only those with the greatest genital tract abnormalities. It is also possible that the presence of FGS plus STIs, particularly trichomoniasis, which tended to be higher in women with Sh infection (p = 0.08), could explain why women with FGS in Zambia had both type 2 and pro-inflammatory immune responses since trichomoniasis can elicit a pro-inflammatory response [150]. Furthermore, analysis of the local mucosal cervical immune phenotype is challenging since there are numerous additional potential confounders, including physiologic changes occurring throughout the menstrual cycle [78,151,152], effect of recent pregnancy [153] or current breastfeeding [79], recent sexual contact, and vaginal cleansing practices [154,155], which were not consistently assessed in the above studies. Nevertheless, studies investigating local mucosal changes are critically important to enhance our understanding of the local cervical immune changes occurring during Sh and why women with FGS or Sh infections may have impaired ability to control genital viral infections such as HIV and HPV [6,11].
In a study of blood and cervical samples of South African women, monocytes were increased in the systemic circulation of women with FGS defined as sandy patches seen on the cervix [107]. While no difference was found in cervical CD4+ T cells or monocytes or their CCR5 expression of the same cohort of women between women with and without FGS, PZQ treatment led to a significant decrease in CD14+ monocytes in both blood and cervical samples. PZQ treatment also led to a decrease in CCR5 expression on CD4+ T cells in blood and cervical samples [107]. The findings of this study provide evidence in favor of the hypothesis that FGS may raise the risk of HIV acquisition, potentially by altering local mucosal cell populations to increase HIV target cell populations.
Jourdan et al [156] performed cervical biopsies to evaluate HIV target cell populations in the female genital tract of Malawian women with Sh infection who had Sh eggs in urine [156]. This study found that the density of CD4+ T cells was higher in cervical biopsies containing viable or calcified Sh ova, compared to cervical biopsies without ova from both endemic and non-endemic Norwegian controls. No difference was observed in the density of CD4+ T cells in tissue comparing viable ova (N = 2) and calcified ova (N = 11), or in Malawian women without presence of Sh ova on biopsies. Importantly, there was no difference in densities of CD4+ T cells in tissue with calcified ova and in biopsies from Norwegian women with chronic cervicitis. The density of CD68+ macrophages was higher in specimens with viable ova than specimens with calcified ova, specimens from Malawian women without ova, and specimens from Norwegian women with healthy cervical tissue [156].
Relatively complementary findings have been reported from one study in men. Men with Sh infection, determined by presence of Sh eggs in urine or semen, were found to have increased leukocytospermia compared to men without Sh infection, which was more pronounced in men with moderate to high egg burden. Similarly, increased seminal eosinophils and IL-10 were seen in men with high egg burden when compared to men without Sh infection [157]. Even though only 5 of the 240 individuals in this study had detectable IL-4 in semen, all had Sh infection with high burden of infection, as measured by concentration of seminal eggs. In the same study, younger men had higher egg secretion in both urine and semen compared to men above age 39 [157], possibly reflecting partial immunity to the helminth with increasing age.
Similarly, Sh disease burden was reported to impact urinary cytokine expression in children with higher Sh urinary egg burden, who had higher urinary levels of IL-6 and lower IL-10, compared to children with lower disease burden [67]. Both these cytokine changes were also associated with hematuria and were not seen in peripheral blood. Furthermore, when the same children were assessed by ultrasound for possible genitourinary pathology, those found to have genitourinary pathology had increased geometric mean intensity (GMI) of IL-6 and lower GMI of TNF-α [67]. This study by Njaanake et al complements genital tract findings and demonstrates that the burden of disease, measured here by concentration of urinary eggs, appears to be a key mediator of extent of tissue pathology and the local mucosal immune milieu.
Overall synthesis of immune studies in Sh infection on local tissue
Collectively, the above studies demonstrate that chronic Sh infection with ova in genitourinary tissues leads to a local inflammatory reaction consisting of Th2 associated cytokines, pro-inflammatory cytokines, and an increased cellular immune response to viable ova comprised of CD4+ T cells and CD68+ macrophages. The intensity of Sh infection appears to be important, with a higher burden of disease triggering a stronger local immune response. Furthermore, individuals with local Sh mediated damage, such as hematuria or pathology seen on genitourinary ultrasound or cervical exam, appear to have higher rates of immune changes compared to individuals without such tissue damage.
S. haematobium infection and the local tissue host immune response in patients with bladder cancer
Three studies focused on tissue immune responses in people with bladder cancer and Sh infection (Table 9).
Table 9. S. haematobium infection and the local tissue immune response in bladder cancer patients.
| Study | Country | Sample size | Sex (female in %) | Age in years | Compartment | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Overall conclusion |
|---|---|---|---|---|---|---|---|
| El-Aal et al 2015 (161) | Egypt | 46 | F (17%) in Sh group | 38–84 | bladder | Compared to Sh negative patients with bladder cancer: ↑ GATA3 ↑ Foxp3 Compared to Sh negative patients with bladder cancer and healthy controls: ↓ STAT4 ↓ CD8+ T cells |
Sh-associated bladder cancer was associated with an increase in Th2 and Treg immune phenotype, while Th1 phenotype decreased. |
| El-Salahy et al 2002 (163) | Egypt | 70 | Not documented | Not documented | bladder | In Sh-associated bladder cancer or cystitis: = IL-6 |
IL-6 was not associated with Sh-bladder cancer or cystitis compared to Sh-uninfected with bladder cancer or cystitis. |
| Mohammed et al 2023 (162) | Egypt | 20–35 (15 with Sh vs 20 healthy PBMCs and 5 healthy bladder tissues) | F (~8%) | 35–73 | bladder Blood |
Compared to patients with Sh negative bladder cancer: ↓ CD3+ T cells ↓ CD8+ T cells Compared to healthy controls: ↑ CD4+ T cells ↑ Tregs ↑ Bregs = B cells (overall) ↓ CD45+ cells ↓ CD8+ T cells |
Sh-associated bladder cancer was associated with a shift towards predominant Th2 versus Th1 immune phenotype and an increase in regulatory immune cell. |
Sh = S. haematobium, T regulatory cells = Tregs, B regulatory cells = Bregs
There are many studies investigating the local gene changes that occur in patients suffering from Sh-associated bladder cancer [158], but only three analyzing changes in the immune phenotype.
In one study, immunohistochemical analysis of bladder biopsies showed increased numbers of cells expressing: (1) signal transducer and activator of transcription 4 (STAT4), which plays a key role in the differentiation of Th1 cells [159], and (2) Foxp3, a marker for Tregs, in patients with Sh-associated bladder cancer, compared to patients with bladder cancer without Sh infection. Cancer patients with Sh infection also had fewer cells expressing GATA3, which is important to generate an optimal Th2 immune response [160]. Two other studies similarly reported that Sh-associated bladder cancer was associated with fewer CD8+ T cells on bladder biopsy specimens, compared to patients with bladder cancer without Sh infection [161,162].
PBMCs from individuals with Sh-associated bladder cancer had lower CD3+ T cells compared to Sh-unassociated bladder cancer, while CD4+ T cells, Tregs, and Bregs were higher in Sh-unassociated bladder cancer compared to healthy controls who did not have Sh infection or bladder cancer [162]. Moreover, investigators reported fewer total CD3+ T cells and T helper cells in these individuals and further demonstrated that individuals with Sh-associated bladder cancer had higher bladder tissue levels of IL-1β, IL-6, and TNF-α, which correlated positively with egg burden, compared to individuals with bladder cancer but without Sh infection [162]. In contrast to this, El-Salahy et al did not find a difference in IL-6 between bladder specimens of patients with bladder cancer or chronic cystitis with or without Sh infection, although they did not report the findings in Sh-associated bladder cancer versus cystitis separately, which could obscure potential differences between the two groups [163].
Overall synthesis of Sh infection and the local tissue host immune response in patients with bladder cancer
The finding that two of these three studies that individuals with Sh infection with bladder cancer have a shift towards a Th2 predominant phenotype, even compared to individuals with bladder cancer without Sh infection, suggests a possible role for Sh-induced immune alterations the carcinogenesis of Sh. Parasite-induced immune dysregulation that leads to a compromise in Th1 immunity might enable malignancy to thrive more easily, and explain at least partially why Sh infection is associated with bladder cancer, since a Th1 immune response is required for cancer control [164].
Experimental models to study effects of Sh infection on immune response
Eight studies have assessed host immune response to Sh using experimental ex vivo organ culture and animal models (Table 10).
Table 10. Experimental models to study effects of S. haematobium infection on immune response.
| Study | Study design | Compartment | Differences in S. haematobium infected compared to uninfected | Overall conclusion |
|---|---|---|---|---|
| Fu et al 2012 (166) | Mice were injected with Sh eggs or control vehicle directly into the bladder wall. | Bladder Serum |
↑ Eotaxin, IL-4, IL-13, TNF-α, KC, MIP-1a, and TGF-β ↑ Eosinophils, neutrophils, macrophages and B cells = IFN-γ and IL-17 ↑ IL-1a, IL-5, VEGF, and IL-17 |
Th2 cytokine responses were increased in Sh-infected mice, particularly IL-4. |
| Fu et al 2015 (170) | Mice were injected with Sh eggs or control vehicle directly into the bladder wall, with or without experimental macrophage depletion. | Bladder Serum |
Macrophage depletion: ↓ AAMs, macrophages, eosinophils, T- and B cells ↓ Eotaxin ↑ IL-1α, IL-3, MCP-1, MCP-3, and MIP-1α ↓ IL-1α, IL-3, IL-4, IL-13, IL-17, IL-23, IFN-γ, Eotaxin, RANTES, MIP-1a, and VEGF |
Macrophage depletion in Sh-infected mice led to multiple downstream effects including change in cellular and cytokine response. |
| He et al 2002 (176) | Organ cultures of healthy human foreskin, obtained by circumcisions, were infected by direct intradermal injection with Sh cercariae. | Foreskin | ↑ IL-1α and IL-10 mRNA ↑ IL-1β, IL-2, IL-10, and TNF-α (macro gene array analysis) = IL-1α (macro gene array analysis) ↓ IL-6, IL-8, IL-15, and IL-18 |
Cercariae induced a local inflammatory immune response in the infected skin tissue ex vivo. |
| Hsieh et al 2014 (167) | Mice with induced E. coli UTI were either injected with Sh eggs or control vehicle directly into the bladder wall. | Bladder | Mice with E. coli UTI with Sh infection versus without: ↑ Macrophages, B cells, and neutrophils ↑ IL-4 ↑ NKT cells specific IL-4 production ↓ T cells (trend) ↓ NKT cells ↓ NKT cell specific IFN-γ production ↓ CD1d expression on macrophages ↓ CD1d expression on dendritic cells |
Sh-infected mice had an elevated Th2 cytokine response, particularly IL-4. IFN-γ, T cells and NKT cells were reduced in Sh-infected mice. |
| Lane et al 1998 (169) | Mice were infected with Sh cercariae via abdominal injections and assessed cytokine response throughout 30 weeks post infection. | Spleen, Mesenteric LNs |
At 14–20 weeks post Sh infection in response to SWAP and SEA stimulation: ↑ IFN-γ, IL-10, and IL-4 After week 20 post Sh infection in response to SWAP and SEA stimulation: ↓ IFN-γ, IL-10, and IL-4 |
Sh-infected mice exhibited a dynamic Th1 and Th2 cytokine response with changing levels over time. |
| Loc et al 2019 (168) | Mice were infected with or without injected Sh cercariae (systemic) and with Sh eggs or control vehicle directly into the bladder wall (local). | Bladder Serum |
In the combined infection model versus Sh-uninfected: ↑ Eotaxin, IFN-γ, IL-4, IL-13, LIF, M-CSF, RANTES, leptin, IL-1α, and TGF-β ↑ leptin ↑ IFN-α, IFN-γ, IL1A, IL-5, IL-13, IL-15, IL-18, IL-23, IP10, M-CSF, and TGF-β |
Systemic and local Sh infection in mice appeared to play a role in the local and systemic immune modulatory effects. |
| Nair et al 2011 (174) | WT or Mta1 KO mice were infected with Sh cercariae via direct percutaneous inoculation. | Liver |
Sh-infected Mta1 KO mice versus WT: 2 and 12 weeks after Sh infection: ↑ mRNA of IFN-γ, IL-2, IL-12, IL-10, and IL-6 ↓ mRNA of CD4 T cells (trend) 8 weeks after Sh infection: ↑ IL-12p70 and IL-10 12 weeks after Sh infection: ↑ IFN-γ, IL-2, IL-12p70, IL-4, and IL-5 ↑ mRNA of IFN-γ, IL-2, IL-12, IL-10, and IL-6 ↓ TNF-α ↓ Eosinophils |
Mta1 appeared to play an important role in the inflammatory responses to Sh egg induced hepatic granulomata in Sh-infected mice. |
| Richardson et al 2014 (172) | Mice were injected with Sh eggs or control vehicle directly into the vaginal wall. | Vaginal | In the first 2 weeks after infection: ↑ T cells and Macrophages ↑ RANTES 2 weeks after infection: ↑ T cells ↑ RANTES 4 weeks after infection: ↑ Macrophages ↑ CXCR4 and CCR5 expressing CD4 T cells ↑ CXCR4 expressing macrophages |
Sh infection in mice led to increased expression of HIV entry molecules (CXCR4, CCR5) on local mucosal HIV target cells. |
Sh = S. haematobium, VEGF = Vascular endothelial growth factor, AAM = Alternatively activated macrophages, KO = knockout, WT = Wildtype
Animal models that recapitulate natural Sh egg deposition during infection must be achieved by injection of eggs and/or cercariae into tissue, which is at least a partial limitation, given that this technique disrupts the normal epithelium in a way that does not occur during natural human infection. To date, no animal model exists that mimics the human cycle of Sh infection, which is likely due to its specificity to humans, unlike S. mansoni which can infect rodents to provide a useful animal model [165]. Sh infection models in mice have shown that the response to Sh is dynamic and involves multiple different immune cell populations as well as a broad range of cytokines and chemokines. All support the well-established type 2 hypothesis in helminth infections, marked by an increase in Th2 type cytokines such as IL-4, IL-5, and IL-13 in mucosal tissue of the bladder in response to Sh eggs [166–168] as well as systemically and in lymphoid tissue [166,168,169].
IFN-γ levels appear to vary depending on tissue type and time since infection. Specific differences between murine models of Sh likely affect the observed immunological consequences. For example, introduction of Sh cercariae via intraabdominal injection only leads to egg disposition in the liver and intestines, as opposed to human infections where egg disposition is mainly in the genitourinary system [169]. Studies have reported an elevation of IFN-γ in lymphoid tissue [169] in the first weeks after intraabdominal cercarial injection, followed by a decline, and an increase in systemic IFN-γ [168] when Sh eggs were directly injected into the bladder wall in combination with intraabdominal cercarial injection. In contrast, Fu et al found decreased systemic IFN-γ levels after Sh bladder egg injection alone without additional cercarial infection [170]. Interestingly, leptin was increased in the local bladder tissue in mice injected with both Sh eggs and cercariae, which has immunomodulatory properties to shift the immune response towards a Th1 phenotype, which is observed during the first weeks of infection before cercariae have developed into adult worms [168,171].
Local Sh egg injection into the bladder or vaginal walls of mice leads to a change in local immune cell populations, with subsequent rises in macrophages, B cells, neutrophils, and eosinophils [166,167,172]. Accompanying these rises, overall local tissue reductions of T cells as well as NKT cells have been reported, with NKT cell specific IFN-γ production and decreased expression of CD1d on antigen presenting cells [167]. These findings align with the decrease in IFN-γ levels seen by Fu et al [170] after direct injections of Sh eggs into the bladder wall.
In this experimental mouse model, Fu et al used intraperitoneal injections to cause a local depletion of macrophages and thereby demonstrated their profound role in the immune response to Sh eggs [170]. After macrophage depletion, mice that underwent direct injection of Sh eggs into the bladder wall developed disrupted cellular and tissue architecture of the resulting granulomata and decreased percentages of macrophages, AAMs, eosinophils, B cells, and T cells overall compared to mice whose macrophages were not disrupted. These mice also developed lower bladder tissue levels of eotaxin, and higher levels of IL-1a, IL-3, MCP-1, MCP-3, and MIP-1a. Furthermore, macrophage depletion led to decreases in systemic levels of numerous cytokines, including cytokines associated with leukocyte recruitment (RANTES, MIP-1a, and eotaxin), Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17 and IL-23) T cell responses, and vascular endothelial growth factor (VEGF). Of note, this increase in VEGF in Sh-infected mice was consistent with findings from a second study [166]. Overall, this work demonstrated the wide-ranging role of macrophages in inducing a breadth of local and systemic immune responses during Sh infection in mice [170]. This is not unexpected since different macrophage subtypes are involved distinct types of immune responses. Notably, this study of macrophage depletion depleted all subtypes simultaneously and did not examine differential effects of various subtype depletions [173].
In another murine model of FGS, mice were injected with Sh eggs into the vaginal wall which led to an influx of different cell populations at different time points after Sh egg injections. In the first two weeks post-injection, vaginal mucosa exhibited a rise of T cells as well as RANTES. This was followed by a decline in T cells and RANTES, while macrophages became elevated starting 4 weeks after infection and persisting through week 8. Both T cells and macrophages in the vaginal wall were found to have increased expression of HIV entry molecules including CXCR4 and CCR5 from week 2 onward [172].
Nair et al used a murine knockout (KO) model to demonstrate a role of Metastasis-associated protein (MTA1) in Sh infection after direct percutaneous inoculation by immersion of the tail in water containing cercariae which typically leads to egg disposition in the liver [174]. MTA1 is a chromatin-bound protein that plays a role in mediating host inflammatory responses to components of virus and bacterial infectious products [175]. Mta1 KO mice had lower Sh infectious burden with fewer worms and eggs in the liver compared to wild-type mice and lower circulating CD4 mRNA, TNF-α and eosinophils. Mta1 KO mice also had a distinct cytokine profile in the liver, with an aberrant Th1/ Th2 cytokine profile marked by elevations in both Th1 and Th2 cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-10) [174]. According to these findings, MTA1 appears to play a significant role in the egg mediated inflammatory response to murine Sh infection in the liver.
Acute infection with Sh cercariae was found to cause local immune response within hours of cercarial skin penetration, as evident in organ cultures of circumcised foreskin of healthy men infected with Sh cercariae by direct injection [176]. The analyzed cytokine expression in the foreskin from 1 to 8 hours after infection demonstrated an increase of IL-1a and IL-10 mRNA levels 4 and 8hrs after Sh infection versus controls, while macro gene array analysis showed decreased IL-6, IL-8, IL-15 and IL-18, elevated IL-1β, IL-2, IL-10 and TNF-α, and no change in IL-1 α in infected foreskin tissue.
Overall synthesis of experimental immune studies in Sh infection
Together, these experimental models demonstrate that there is a complex and dynamic immune response to Sh infection, consisting of an initial mixed Th1 and Th2 response followed by a dominant Th2 response in the local tissue and systemically [168,170]. These animal findings largely cohere with human data and provide greater insight into the immune response. These studies extend insights into the response over time after initial infection and allow for an enhanced understanding of the biological mechanisms through in vivo experiments, such as the involvement of Mta1 and macrophages in the immunopathology of Sh, and through heightened control in comparison to human studies. However, it is important to highlight that there is still no animal model of Sh infection that completely resembles human Sh infection. To mimic human disease in which worms reside in the genitourinary tract and eggs are deposited in the genitourinary system, eggs must be directly injected into the genitourinary tissue since infection with cercariae only leads to egg disposition in liver and intestines in animals. Despite the importance of animal studies, it is highly likely that the presence of adult worms in humans with egg secretion and proteolytic passage of the eggs through tissue to reach their destination in the bladder cause a far more complex immune response that so far cannot be replicated in animal models.
S. haematobium infection and host gene expression
In the next section, we turn to described effects of Sh infection on gene and protein expression. A total of 26 studies are included in this section. Twelve studies investigated the local tissue host gene and protein expression changes in Sh-associated bladder cancer and three studies investigated noncancerous Sh infection. Four studies focused on changes in systemic gene expression in individuals with Sh infection and seven studies focused on Sh experimental techniques in cell cultures and animal models.
S. haematobium infection and host mucosal gene and protein expression in S. haematobium associated bladder cancer
In total, 12 studies have compared gene expression in people with bladder cancer with and without Sh infection (Table 11).
Table 11. S. haematobium infection and mucosal gene and protein expression in S. haematobium associated bladder cancer.
| Study | Country | Sample size | Sex (female in %) | Age in years | Compartment | Differences in individuals with bladder cancer and S. haematobium infection compared to individuals with bladder cancer without S. haematobium infection |
Overall conclusion |
|---|---|---|---|---|---|---|---|
| Abdulamir et al 2009 (179) | Jordan, Syria | 148 | F (14%) | 38–72 | Bladder | In bladder cancer: ↑ p53, Bcl-2, c-myc, and Rb = p16, Ki-67, and EGFR In chronic cystitis (no bladder cancer): = p53, Bcl-2, c-myc, Rb, p16, Ki-67, and EGFR |
Sh-associated bladder cancer had a distinct genetic profile compared to Sh-negative bladder cancer with elevated p53 expression, suggesting tumor aggressiveness. There was no difference in gene expression in patients with chronic cystitis with or without Sh infection. |
| Bernardo et al 2016 (196) | Portugal, Angola | 9 | F (67%) | 18–82 | Urine | Proteins associated with: ↑ immune response and inflammation ↑ negative regulation of endopeptidase activity Sh infection (with and without cancer): ↑ oxidative stress ↑ immune defense systems responsible for microbicide activity |
Sh infection with or without cancer led to increased oxidative stress and immune system activation in the GU system. Sh-associated cancer led to increased immune and inflammatory response. |
| Bernardo et al 2020 (180) | Portugal, Angola | 142 | F (30%) | 54–75 | Bladder | ↑ ERα ↑ p53 ↑ proliferation ↓ ERβ In comparison to Sh negative bladder cancer and Sh positive non-malignant bladder lesions |
Increased p53 expression in Sh-associated bladder cancer suggests aggressive tumor behavior. ERα expression was increased in Sh-associated bladder cancer. |
| El-Salahy et al 2002 (163) | Egypt | 70 | Not documented | Not documented | Bladder | = cytokeratin 19 = cytokeratin-20 |
There was no difference in cytokeratin -19 and -20 expression, which have been associated with bladder cancer. |
| Hassan et al 2013 (193) | Sudan | 194 | F (39%) | 50–84 | Bladder | ↑ COX-2 ↑ iNOS |
Sh infection, including cancer and cystitis, were both associated with increased COX-2 and iNOS. |
| Elmansy et al 2012 (187) | Egypt | 75 | F (16%) | 20–80 | Bladder | ↑ Fas and FasL = cytokeratin-19 and -20 |
Sh-associated bladder cancer had increased Fas and FasL expression. This may lead to apoptosis of infiltrating anti-tumor lymphocytes promoting cancer survival. There was no difference in expression of cytokeratin-19 and -20, which have been associated with bladder cancer. |
| Khayoon et al 2021 (192) | Iraq | 50 | F (22%) | 21–70 | Bladder | ↑ COX-2 | Inflammatory protein COX-2 was increased Sh-associated bladder cancer. |
| Mursi et al 2013 (185) | Egypt | 70 | Not documented | Mean 45–60 | Bladder | ↑ p63 expression | Sh infection was associated with increased expression of p63 in bladder tissue of chronic cystitis and cancer. |
| Pycha et al 1993 (183) | Egypt | 220 | F (23%) | 28–83 | Bladder | = p53 | P53 was expressed similarly among Sh-associated and non-associated bladder cancer. |
| Salim et al 2008 (194) | Egypt | 36 | F (78%) | 39–72 | Bladder | ↑ iNOS ↑ 8-OHdG, OGG1, APE1, and ssDNA = eNOS ↑ eNOS in Sh SCC compared to Sh UC |
Sh-associated cancers had increased oxidative stress and DNA damage. |
| Shams et al 2013 (184) | Egypt | 125 | F (20%) | 49–68 | Bladder | ↑ c-KIT | C-KIT expression was increased Sh-associated bladder cancer. |
| Sheweita et al 2001 (189) | Egypt | 41 | F (5%) | 42–70 | Bladder | ↑ carcinogen-metabolizing enzymes (Cyp450, Cyp b3, Aryl hydrocarbon hydroxylase, DMN-N-demethylase I activity, 12, Ethoxyresorufin-O-deethylase, Pentoxyresorufin-O-depentylase) ↑ level of free radicals ↑ GST ↑ thiobarbituric acid-reactive substances ↓ GR and GSH |
Bladder cancer associated with Sh infection exhibited distinctive characteristics when compared Sh negative cancer with multiple changes associated with a malignant environment. |
Sh = S. haematobium, SCC = squamous cell carcinoma, UC = urothelial carcinoma, ER = estrogen receptor, COX-2 = Cyclooxygenase-2, GST = glutathione S-transferase, GR = glutathione reductase, GSH = Glutathione, 8-OHdG = 8-hydroxy-2-deoxyguanosine, eNOS = endothelial NOS, OGG1 = 8-oxoguanine-DNA-glycosylase, APE1 = apurinic/apyrimidinic endonuclease, ssDNA = single strand DNA, CK = Cytokeratin
Bladder carcinoma typically involves alterations in several genes including the tumor suppressor genes p53, p63, retinoblastoma (Rb), and p16, as well as oncogenes c-myc and epithelial growth factor (EGFR), which are all associated with aggressive and invasive bladder carcinomas. Antiapoptotic protein BCL-2 [177] and the proliferative protein ki-67 [178] have also been linked to aggressive bladder carcinoma.
Three studies have quantified p53 expression in bladder carcinomas. Two studies reported higher expression of p53 in individuals with Sh-associated bladder cancer compared to Sh-unassociated bladder cancer, in bladder specimens [179] and urine [180], suggesting tumor aggressiveness [177,181,182]. In contrast, p53 was not more overexpressed in Sh-associated bladder cancer specimens than in Sh-unassociated bladder cancer specimens in patients from Egypt [183].
In addition to increased p53 expression, Abdulamir et al reported more frequent expression of BCL-2, c-myc, and Rb in bladder biopsy specimens in Sh-associated bladder cancer in Jordan and Syria [179]. Further, Sh-associated cancer exhibited higher grade and increased invasiveness compared to Sh-unassociated bladder cancer [179]. Bernardo et al found, in addition to increased p53 expression, increased estrogen receptor (ER) α expression in Angolese Sh-associated bladder cancer specimens, which was absent in Sh-unassociated bladder cancer specimens from Angolese and Portuguese patients without Sh exposure. Furthermore, ERα expression was positively correlated with numbers of Sh eggs found in bladder cancer specimens [180]. This increased ERα expression in Sh-associated bladder cancer appears to be unique to the association with Sh infection.
Bladder tissue obtained from radical cystectomies of patients with squamous cell carcinoma in Egypt showed higher expression of the proto-oncogene c-KIT in carcinomas associated with Sh, compared to those not associated with Sh [184]. Furthermore, in the same study, c-KIT expression was also associated with increased tumor size and distant metastasis, arguing that Sh-associated squamous cell carcinoma is more aggressive than Sh-unassociated squamous cell carcinoma [184]. Another Egyptian study found increased p63 in bladder specimens from people with Sh infection with either chronic cystitis or bladder cancer, suggesting that p63 may be linked more generally to Sh-associated tissue disease rather than specifically to cancer [185]. The above four studies highlight that there are distinct differences in the genetic alterations occurring in Sh-related and unrelated bladder cancer [179,180,184,185].
The death receptor Fas (Apo1/CD95) and FasL system is recognized as a major pathway for the induction of apoptosis in vivo, and its blockade plays a critical role in carcinogenesis and progression in several malignancies [186]. Expression of both Fas and FasL was higher in Sh-associated bladder cancer samples than in non-Sh-associated bladder cancer [187]. A potential mechanism is that the acquisition of the functional FasL may induce apoptosis of anti-tumor T lymphocytes during tumor progression. Neither this study nor another found a change in cytokeratin-19 or -20 expression, which have also been associated with bladder cancer, in Sh-associated versus non-associated bladder cancers [163,187].
The enzymes glutathione S-transferases (GST) and glutathione reductase (GR) are a group of inducible enzymes that support detoxification of many different xenobiotics in mammals. Decrease in GST activity and depletion of glutathione (GSH) levels might potentiate the harmful effects of environmental toxins and carcinogens. Consequently, inducers of GSTs are generally considered to be protective compounds against malignancy [188]. A study conducted in Egypt showed that bladder biopsies of individuals with Sh-associated bladder cancer had higher levels of GST as well as decrease in GR and GSH levels. All of these changes would contribute to poorer ability to attenuate environmental toxins and carcinogens, thereby increasing multiple carcinogen-metabolizing enzymes and free radicals and enhancing carcinogenic potential [189].
Cyclooxygenase-2 (COX-2) is an important pro-inflammatory mediator that is present only at low levels during normal conditions but is robustly induced after an insult such as infection or injury [190]. COX-2 expression, together with inducible nitric oxide synthetase (iNOS) which is associated with oxidative stress [191], was higher in bladder biopsies of Sh-associated versus non-Sh-associated bladder cancer patients and in Sh-associated versus non-Sh-associated benign cystitis [192]. A second study similarly reported higher iNOS in Sh-associated bladder cancer tissue [193,194]. Further, this second study found that levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker for DNA damage [195], were increased in tissue of Sh-associated bladder cancer [194]. Biopsies from Sh-associated cancers also had higher expression of DNA-repair genes, including 8-OHdG and apurinic/apyrimidinic endonuclease, and higher formation levels of single strand DNA [194]. Together, these two studies suggest a strong correlation between Sh infection and increased levels of oxidative stress accompanied by continuous DNA damage, necessitating increased DNA repair.
Proteome profiling of urine samples of 9 participants with either Sh-associated bladder inflammation or cancer, or Sh-unassociated bladder cancer, showed an increase in proteins involved in immunity and inflammation as well as negative regulation of endopeptidase activity in Sh-associated bladder cancer. Samples from participants with Sh infection, whether inflammation or cancer, had higher urinary proteins associated with oxidative stress and immune defense systems responsible for microbicide activity, in comparison to Sh-uninfected participants with bladder cancer [196].
Overall synthesis of gene expression studies in Sh infection and bladder cancer
Together, the above studies highlight the unique genetic changes associated with immune activation, chronic inflammation, and fibrosis in Sh infection. These changes in gene expression may both predispose to carcinogenesis, and then be further modulated by carcinogenesis, resulting in high-grade and aggressive bladder cancer.
S. haematobium infection and mucosal gene expression of the host
A total of three studies have compared local mucosal gene expression in people with and without Sh infection, without cancer (Table 12).
Table 12. S. haematobium infection and mucosal gene and protein expression.
| Study | Country | Sample size | Sex (female in %) | Age in years | Compartment | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Overall conclusion |
|---|---|---|---|---|---|---|---|
| Dupnik et al 2019 (149) | Tanzania | 57 | F (100%) | 20–35 | Cervical | ↑ MMP-2, MMP-16, ABP4 (encoding fatty acid binding protein 4, TGM3 (transglutaminase 3;), MB (myoglobin), SERPINB11 (serpin family B member 11), TEPP (testis, prostate and placenta expressed), SLC26A2 (solute carrier family 26 member 2), SERPINA3 (serpin family A member 3; fold change), and AKR1B15 (aldo-keto reductase family 1 member B15) ↓ MMP-3 (TIMP-3) and SLC26A2 (solute carrier family) |
Sh infection led to gene alterations in the cervix of infected women which are associated with loss of epithelial barrier integrity and malignancy. |
| Habib et al 2006 (198) | Egypt | 26 | F (27%) | 20–46 | Liver | ↑ AFB1 and p53 | Sh infection led to pro-oncogenic genetic changes in the liver. |
| Zhong et al 2013 (199) | Ghana | 57 | F (47%) | 18–80 | Urine | Individuals with Sh infection with bladder damage on US: RASSF1A methylation and TIMP-3 methylation |
Sh infection led to methylation and hence to a decreased expression of tumor suppressor genes followed by tissue damage. |
Sh = S. haematobium, MMP = metalloproteinase, TIMP = tissue inhibitor metalloproteinase, AFB1 = aflatoxin B1, US = ultrasound
110 genes were differently expressed in cervical cytobrush samples from Tanzanian women with or without Sh infection. In this study, the transcript count showed that 7 out of 8 genes had lower expression in women with Sh infection. The top altered canonical pathway was “inhibition of matrix metalloproteinases”, with increased expression of metalloproteinases (MMP) MMP-2 and MMP-16 as well as decreased expression of tissue inhibitor MMP-3 (TIMP-3), followed by: “colorectal cancer metastasis signaling”, “glioma invasiveness signaling”, and “bladder cancer signaling.” Together, these results suggest that Sh infection is associated with compromised integrity of the genital mucosal barrier in women with Sh infection, and with genetic changes that could promote malignancy [149].
In a study of genetic changes in liver biopsies of patients with Sh and/or S. mansoni infection, biopsies with fibrosis were compared to normal liver biopsies without schistosomiasis. People with Sh mono-infection or Sh/ S. mansoni co-infection had elevated aflatoxin B1 adducts, known hepatic carcinogens [197], and those with Sh mono-infection had more p53 mutations than S. mansoni mono-infected or healthy controls [198]. Together, this suggests that entrapped Sh eggs can lead to pro-carcinogenic changes in the liver in addition to the bladder, while S. mansoni eggs appear to be less carcinogenic.
Methylated RASSF1A and TIMP3 genes, both tumor suppressor genes that have been documented to be elevated in bladder cancer and damage [199], were found to be increased in the urine of individuals with Sh infection who had ultrasound-confirmed bladder damage compared to individuals without Sh infection from the same endemic region in Ghana. DNA methylation of two tumor suppressor genes in urine samples that correlated with Sh induced bladder damage suggested that these might be early signs of bladder transformation that occurred in advance of bladder cancer. If this is correct, these methylated genes could serve as predictive biomarkers in individuals with Sh infection for genitourinary damage and cancer risk.
S. haematobium infection and systemic gene expression in blood
Four studies compared systemic gene expression changes by examining whole blood transcriptional profiles in people with and without Sh infection (Table 13).
Table 13. S. haematobium infection and systemic gene expression in blood.
| Study | Country | Sample size | Sex (female in %) | Age in years | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|
| Dupnik et al 2018 (205) | Tanzania | 33 | F (60%) | 21–33 | Different gene expression:
↑ Notch signaling genes (including mindbomb ubiquitin ligase, neuralized E3 ubiquitin protein ligase 1) |
N/A |
Sh infection led to unique genetic changes including cell signaling and survival and immune responses. Women with Sh infection had more changes in gene expression in comparison to men with Sh infection. |
| *Hartgers et al 2008 (200) | Ghana | 120 | F (46%) | 5–14 | ↓ TLR2 mRNA and SOSC-3 mRNA | N/A | Individuals with Sh infection had decreased expression of TLR2 and SOCS-3 mRNA, identifying a molecular link between Sh infection and altered immune response. |
| *Labuda et al 2020 (58) | Gabon | 17 | Male and female (% not documented) | School-children | ↑ 140 genes ↑ cell adhesion genes ↑ oxidative phosphorylation ↑ citrate/TCA cycle ↓ 180 genes ↓ NK cells, DCs and monocytes |
↑ 34 genes ↑ immune response ↑ T cell anergy ↑ EGR2 and EGR3 ↑ cell cycle oxidative phosphorylation ↓ 158 genes ↓ citrate/TCA cycle 7 months after treatment |
Sh infection led to molecular changes, including increased genetic pathways important for Th2 immunity, cell adhesion and decrease in pertinent immune cell populations. PZQ treatment led to multiple changes in gene expression, but did not completely resolve these. |
| Shariati et al 2001 (207) | Malia, Nigeria | 33 | F (3%) | 19–37 | ↑ VEGF | N/A | Sh infection led to increased VEGF expression which is associated with bladder cancer. |
Sh = S. haematobium, TLR = toll like receptor, SOCS = suppressor of cytokine signaling, EGR = early growth response genes
*Studies included participants with additional parasitic infections.
In a study conducted in Ghana, mRNA expression of TLR2 was downregulated in whole blood of children with Sh infection compared to those without infection [200]. TLR2 recognizes a wide range of pathogenic molecules and is able to induce a Th1 or Th2 immune response [201] and suppressor of cytokine signaling 3 (SOCS-3), which leads to increased Th2 differentiation and altered IL-2 and IFN signaling. The children infected with helminths, including Sh, had lower frequencies of reactions to dust hermits tested by a mite allergen skin prick test [200] in line with prior studies describing decreased allergic reactions in S. mansoni [202] and helminth infected individuals [203]. Further, the lower allergic reactions in those with Sh were accompanied by lower expression of genes associated with the innate immune system, particularly TLR2 and SOCS-3, which trigger allergic inflammation and IFN response. The impaired IFN response in Sh infection may connect Sh infections not only to a reduced risk of atopy but also to an increased risk of viral infections. This research underscores the unique genetic modulation in Sh infection compared to other helminth infections, emphasizing the importance of understanding the unique characteristics of Sh infection apart from other helminths.
In the previously mentioned study by Labuda et al [58], analysis of the whole blood transcriptome identified 320 differentially expressed genes between 8 Gabonese schoolchildren with Sh infection and 9 without Sh infection, while after PZQ treatment only 4 genes remained differently expressed between the two groups. Gene ontology analysis showed increase in processes associated with cell adhesion in those with Sh infection, whereas PZQ treatment resulted in downregulation of immune responses and cell cycle genes [58]. Furthermore, children with Sh infection had reduced gene signatures for NK cells, DCs, and monocytes, while T cell activation, miotic cell cycles, and pathways involved in oxidative phosphorylation and the citrate/TCA cycle were upregulated. All these oncologic changes suggest induction and maintenance of type 2 immunity [204]. The differences in NK cell signatures and mitotic cell cycle were reversed, and immune activation was overall reduced post-PZQ therapy [58]. Chemotherapy with PZQ also led to upregulation of oxidative phosphorylation and downregulated citrate/TCA cycle, and transcriptional factors for the induction of T cell anergy, including early growth response genes 2 and 3 [58]. Overall, this study indicated multiple changes occurring on a molecular level during Sh infection, consistent with increased cell adhesion and type 2 immunity, which was only partly reversed by PZQ treatment. A limitation of this study is that schoolchildren in both groups also had different prevalence of co-infections with other parasites, which included Plasmodium falciparum, Ascaris lumbricoides, Trichuris trichiura, and hookworm. These co-infections may have influenced the transcriptome profiling of the individuals.
Transcriptional profiles of PBMCs in a Tanzanian cohort showed 383 differentially expressed genes between those with and those without Sh infection, of which 270 genes correlated with CAA values. Interestingly, 29 genes were differentially expressed in men with Sh infection, and 2,142 genes women with Sh infection compared to men and women without infection, respectively [205]. Ingenuity pathway analysis identified altered networks associated with development, cell death and survival, cell signaling, and immunologic disease pathways. Genes which were differentially expressed were associated with p53 signaling, including BCL-2, as well as with histone transcription. Furthermore, expression of multiple genes involved in Notch signaling were increased. This study emphasizes not only changes in genetic expression occurring during Sh infection, but furthermore the importance of host factors, such as sex, that impact this host response to Sh.
Individuals with Sh infection (n = 15) who had lived in Spain for 6 months after immigrating from West Africa had increased VEGF expression on whole blood ELISA testing, which has been associated with bladder cancer, compared to those without Sh infection (n = 18) [206]. While the study’s size limits interpretability, the reported rise in VEGF aligns with findings by Fu et al in Sh-infected mice [166], despite the two prior studies not reporting changes in VEGF expression.
Overall synthesis of systemic gene expression studies in Sh infection
Together, these gene expression data triangulate and substantiate immune changes observed in studies described above. Both groups of studies indicate changes in type 2 immune phenotype, cell signaling, and survival. Besides the known role of sex differences in the immune response, this literature demonstrates that they also affect genetic modulation in response to Sh infection [205]. This underscores the importance of evaluating host response to infection, including host gene expression, by sex.
Experimental models to study S. haematobium infection and host gene, protein expression, and cell cycle dynamics
Seven studies assessed changes in gene expression associated with Sh utilizing experimental models (Table 14).
Table 14. Experimental models to study effects of S. haematobium infection on gene, protein expression and cell cycle dynamics.
| Study | Study design | Compartment | Differences in S. haematobium infected compared to uninfected | Overall conclusion |
|---|---|---|---|---|
| Botelho et al 2009 (215) | Chinese hamster ovary cells co-cultured with Sh total antigen | Ovarian cell line | ↑ S phase and G2/ M phase ↓ G02/ G1 phase ↑ Bcl-2 gene (anti-apoptotic) ↓ p27 gene (tumor suppressor) |
Sh total antigen led to increased proliferation and decreased apoptosis through changes in cell cycle and gene expression. |
| Botelho et al 2013 (210) | Mice were administered Sh total antigen versus saline as control transurethrally into the bladder. | Bladder | ↑ Dysplastic bladder lesions ↑ KRAS (20% of mice with dysplastic lesions) ↑ Inflammatory and lymphocyte infiltrate ↑ Monocytes |
Most bladders of mice exposed to Sh total antigen developed inflammatory infiltrates. Half developed dysplastic lesions and 20% of these with KRAS mutation |
| Chala et al 2017 (209) | Mice were either injected with Sh eggs into the bladder wall or received chemical carcinogen (BBN) administered through drinking water, or received both. | Bladder | Mice injected with Sh eggs alone: ↑ Ki-67 in lymphocytes (week 4 and 12) ↑ p53 in urothelial cells (week 4) Mice injected with Sh eggs and BBN: ↑ Ki-67 in urothelial cells (week 20) ↑ Vimentin urothelial cells (week 20) ↑ p53 urothelial cells (week 20) ↓ E-Cadherin in urothelial cells (week 20) Mice with BBN alone: ↑ Vimentin urothelial cells (week 20) |
Mice injected with Sh eggs had increased Ki-67 in lymphocytes and elevated p53 in urothelial cells. Mice injected with eggs and carcinogen had the most evident changes concerning for possible malignant transformation. |
| Mbanefo et al 2020 (214) | WT or IL-4R KO Mice were either injected with Sh eggs or a sham injection into the bladder wall. | Bladder | WT mice with Sh eggs: ↑ S phase and G2/ M phase IL-4R KO mice with Sh eggs: ↓ S phase |
Sh eggs induced cell cycle changes in the bladder in an IL-4 dependent fashion. |
| Osakunor et al 2022 (212) | Mice were injected with Sh eggs or control extract directly into the bladder wall. | Bladder | Proteins associated with: ↑ carcinogenesis (STEAP4, Pla2g7, Dab2, Fkbp14, Stab1, Loxl2, Prpf3, Ltbp3, Nob1, Raly, Gpx8) immune and inflammatory responses (STEAP4, Serpina3n, Dab2, C8a, Pecam1, Prpf3, Dnajc7) protein translation or turnover (Rps9, Rpl5, Rpl26, Rps13, Rps3a, Rpl23) oxidative stress responses (Pla2g7) ↑ epithelial barrier integrity (Ptpn2) glucose metabolism (Tbc1d4) ↓ carcinogenesis (Cryl1, Usp11, Gnao1, Gnao1, Grhpr, Ppp1r14a, Hopx) tumor suppression (Usp11, Gas1, Cbr1) ↓ cell survival (Bcl-2) ↓ structural integrity and cell adhesion (Itgb3, Itga1, Itga7, Armc1, Usp11, Dmd, Mapre3) |
Multiple changes in proteome expression were identified in mice with Sh eggs associated with carcinogenesis, inflammation, and loss of epithelial barrier integrity. |
| Ray et al 2012 (213) | Mice were injected with Sh eggs or control vehicle directly into the bladder wall. | Bladder | By week 1: ↑ 279 genes ↓ 22 genes By week 3: ↑ 1001 genes ↓ 570 genes By week 5: ↑ 794 genes ↓ 308 genes Genes related to: ↑ Inflammation (IL-4, IL-4-induced 1, IL-1β, IL-6, IFN- inducible proteins (IFI30 and IFI47), TGF-β, IL-13 receptor alpha 2, IL-10 receptor alpha, and cytokine inducible SH2- containing protein) ↑ Markers of macrophages (macrophage-expressed gene 1 (general macrophage marker) Markers of AAM (arginase, Ym1 (CHI3L3), and mannose receptor C type 1) ↑ Chemokines (CCL4 (MIP-1β), CCL5 (RANTES), CCL11 (eotaxin) and CXCL1 (KC)) ↑ Carcinogenesis (growth factor-, oncogene-, and mammary tumor-related genes) ↓ claudins and junctional adhesion molecules Changes over time: ↑ cytokine-cytokine receptor pathways, peaked at week 1 and 3 ↑ B cell receptor signaling pathway, peaked at week 5 ↓ claudins and junctional adhesion molecules, week 3 |
Sh egg disposition in the bladder led to many genetic changes in the bladder including differential transcription of immune response-, fibrosis-, cancer-, and epithelial barrier-related genes. |
| Sheweita et al 2003 (208) | Organs of hamsters with and without transdermal Sh cercarial infection were assessed at different timepoints after Sh infection over the course of 10 weeks. | Bladder | ↑ GST (week 2, 4, 6) ↓ GST (week 8, 10) ↑ GSH (week 2, 6) ↓ GSH (week 4, 8, 10) ↑ GR (week 8) ↓ GR (week 10) ↑ Free radicals (week 2, 4, 6, 8, 10) |
Decreased GST activity and increased free radicals were seen in most organs, but most pronounced in bladder which could indicate an early mechanism of Sh induced organ damage. |
| Kidney | ↑ GST (week 6, 10) ↓ GSH (week 4, 8, 10) ↑ GR (week 2, 4, 6, 8) Free radicals (week 2, 4, 6, 8, 10) |
|||
| Liver | = GST ↓ GSH (week 6, 8, 10) ↑ GR (week 2, 4) ↓ GR (week 6) |
|||
| Spleen | ↑ GSH (week 4, 6, 10) ↓ GST (week 2, 6, 10) ↑ GR (week 4, 8) ↓ Free radicals (week 6, 8, 10) ↑ Free radicals (week 2, 4) |
|||
| Lung | ↑ GST (week 8, 10) ↓ GSH (week 8, 10) ↑ GSH (week 2, 4, 6) ↑ GR (week 2, 4, 6, 8, 10) |
Sh = S. haematobium, GST = glutathione S-transferase, GR = glutathione reductase, GSH = Glutathione, BBN = N-butyl n-(4hydroxybutyl) nitrosamine, AAM = alternatively activated macrophage, WT = wild-type, IL-4R = IL-4 receptor alpha, KO = knockout
A study that assessed activity of GST and GR, and levels of GSH, in multiple organs of transdermally infected hamsters with Sh cercariae with successive sampling for up to 10 weeks post infection showed substantial variation depending on the specific organ as well as the time point after infection [207]. There was no change in uninfected hamsters used as a control at each time point. Activity of GST and GR, as well as GSH levels, increased in the studied organs (liver, bladder, spleen, and lung) at some time point post-infection followed by a partial decrease in the liver and bladder. Only the bladder was found to have a decrease in all three (GST and GR activity, and GSH levels) at the last two stages post-infection. Free radicals remained elevated throughout only in the bladder and kidneys. This demonstrated reduction, particularly of GST activity in the bladder during the later stages of Sh infection, and the associated high levels of free radicals, could provide new insights on Sh induced damage to the bladder and other organs [207].
A mouse study investigated effects of injection of Sh eggs directly into the bladder, versus administration of carcinogen N-butyl n-(4-hydroxylbutyl) nitrosamine through drinking water, which is a known carcinogen, versus eggs plus carcinogen. Mice injected with eggs alone had higher expression of activation marker Ki-67 in lymphocytes and p53 after 4 weeks, and Ki-67 remained elevated at 12 weeks. The eggs plus carcinogen group was the only group with increased expression of Ki-67 in urothelial cells, which was found at week 20. Additionally, this group had elevated p53 expression and vimentin at week 20, while E-cadherin was decreased [208]. This suggests that Sh eggs in bladder tissue led to upregulation of lymphocyte proliferation, yet led to genetic changes worrisome for urothelial transformation only when combined with a known carcinogen.
In a study by Botelho and colleagues [209], half of the mice that were exposed to Sh total antigen, infused directly into the bladder through the urethra, developed histologically dysplastic bladder lesions. Almost all Sh-exposed mice were found to have inflammatory infiltrates and elevated lymphocytes in the bladder tissue, compared to control mice. Furthermore, 20% of the dysplastic bladder lesions were found to have a KRAS gene mutation [209], which is commonly found in bladder cancers [210]. This implies that Sh presence may upregulate KRAS, increasing the risk of developing bladder cancer. It is unclear if this is specific to Sh or a general response in bladder epithelium to carcinogens, including Sh antigens. A control group with a non-Sh carcinogen-induced bladder transformation would have added insight into differences between Sh-mediated and other carcinogenic mediated bladder lesions.
Proteome profiling of bladders of mice that underwent local injection of Sh eggs into the bladder walls showed differential expression of proteins important for immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced epithelial barrier integrity, and carcinogenic pathways 7 days after eggs were administered [211]. Overall, the bladders of mice with Sh egg injection were found to have 45 differentially expressed proteins (25 upregulated and 20 downregulated) compared to mice that were injected with uninfected hamster liver and intestine tissue extract into their bladder walls as controls.
Microarray-based comparisons of Sh egg versus control vehicle-injected bladders demonstrated differential gene transcription changes over time with 301 changes at 1 week, a peak of 1571 changes at 3 weeks, and 1012 genetic changes by 5 weeks post egg injection [212]. The presence of Sh eggs in the bladder of mice prompted an increase of genes related to inflammation, particularly cytokine-cytokine receptor pathways dominated by Th2 cytokines, and macrophage function-associated gene transcription. Simultaneously, extracellular matrix remodeling-related gene transcription was differentially modulated over time, and pathways analysis pointed to differential transcription of multiple genes implicated in carcinogenesis [212]. Sh eggs also dampened transcription of epithelial barrier genes, such as tight junctions and uroplakins, which may cause compromises in the urothelial barrier [212]. These findings indicate that the presence of Sh eggs in bladder tissue not only provoke a strong local, largely Th2 immune response, but also enhance genes associated with extracellular matrix remodeling suggesting fibrosis development, compromised epithelial barrier integrity, and carcinogenesis.
Sh egg bladder injection in wild-type mice increased mitotic cells, with a higher proportion of urothelial cells in S phase and G2/M phase [213], which was also seen after Sh total antigen administration to a Chinese hamster ovary cell line [214]. This pro-miotic effect was diminished in IL-4 receptor-deficient mice [213], indicating an IL-4-dependent mechanism. In addition to alterations in cell cycle phases, Sh total antigen administration to the Chinese hamster ovary cell line resulted in decreased apoptosis with increases in anti-apoptotic gene Bcl-2, and in tumor suppressor gene p27. These studies suggest that Sh may lead to bladder cell cycle skewing in an IL-4-dependent fashion.
Overall synthesis of experimental gene expression studies in Sh infection
Taken together, these experimental studies conducted in animal models and cell lines demonstrate that Sh infection mimicked by the presence of Sh eggs or antigens can lead to changes in enzyme and protein expression, and cell cycle changes, which are linked to an environment favorable for inflammation, compromised epithelial barrier, and carcinogenesis. These studies emphasize not only the role of Sh infection in the development of bladder cancer, but also provide insight into the pathophysiologic changes that underlie Sh-linked bladder cancer, as well as possibly facilitate entry of additional pathogens through a compromised epithelial barrier.
S. haematobium infection and the host microbiome
A total of six studies compared microbiome changes in gut, urine, and cervicovaginal microbiota during Sh infection (Table 15).
Table 15. Effects of S. haematobium infection on the host microbiome.
| Study | Country | Sample size | Sex (female in %) | Age in years | Microbiome compartment | Differences in individuals with S. haematobium infection compared to individuals without S. haematobium infection |
Effect of praziquantel treatment | Overall conclusion |
|---|---|---|---|---|---|---|---|---|
| Adebayo et al 2017 (216) | Nigeria | 70 | F (49%) | 15–65 | Urine | ↑ OTUs in advanced Sh cases ↑ Firmicutes proportion ↓ Diversity index in advanced Sh cases ↓ Proteobacteria proportion |
N/A | There were unique differences in the urinary microbiome between individuals with Sh infection alone. |
| Ajibola et al 2019 (26) | Nigeria | 49 | F (16%) | 11–15 | Gut (fecal) | ↑ Abundance of Proteobacteria, Moraxellaceae, Veillonellaceae,Pasteurellaceae, and Desulfovibrionaceae ↓ Abundance of Firmicutes and Clostridiales Differences in beta but not alpha diversity |
N/A | Adolescents with Sh infection had a shift in the gut microbiome consistent with dysbiosis and gut inflammation. |
| Bullington et al 2021 (229) | Tanzania | 43 | F (100%) | Median = 34 | Cervicovaginal | ↑ Alpha diversity with infection intensity ↑ Beta diversity at follow-up ↓ Trend of abundance of Lactobacillus with infection intensity |
↑ Alpha diversity if Sh positive vs. Sh negative (trend) 3 months after treatment |
Sh infection with high intensity was associated with more diverse cervicovaginal bacterial communities than women without Sh infection. |
| Kay et al 2015 (128) | Zimbabwe | 139 | F (47%) | 6 mo– 13 yo | Gut (fecal) | ↑ OTU species diversity ↑ Abundance in 5 Prevotella OTU ↑ Nonsignificant in 22 OTU |
No effect on prior seen microbiome changes in Sh infected 3 months after treatment |
Children with Sh infection had significant gut microbiome changes which were refractory to PZQ treatment. |
| Osakunor et al 2020 (218) | Zimbabwe | 113 | F (50%) | 1–5 | Gut (fecal) | ↑ Pseudomonas, Stenotrophomonas, Derxia, Thalassospira Aspergillus, Tricholoma, and Periglandula ↓ Azospirillum |
No difference was seen in individuals with a history of PZQ treatment | Children with Sh infection had distinct differences in their fecal microbiome compared to children without Sh infection. |
| Sturt et al 2021 (230) | Zambia | 188 | F (100%) | 18–31 | Cervicovaginal | No differences in key cervicovaginal species (Lactobacillus crispatus, Lactobacillus iners, Atopobium vaginae, and Candida albicans) Women with FGS and moderate/ high genital Sh burden (≥2 Sh qPCR-positive genital specimens): ↑ Trichomonas vaginalis and Garderella vaginalis |
N/A | Women with Sh infection with moderate/ high genital Sh burden were more commonly infected T. vaginalis and G. vaginalis. |
Sh = S. haematobium, PZQ = Praziquantel, OTU = operational taxonomic units, FGS = female genital schistosomiasis
In four of these, Firmicutes, Proteobacteria, and Bacteroidetes were the most abundant bacteria phyla in both gut and urine microbiota in individuals with and without Sh infection [26,215–217].
Three studies focused on differences in the gut microbiome through analysis of stool samples of individuals with and without Sh infection. Sh adult worms reside in the vasculature of the genitourinary system, and eggs migrate preferentially into the genitourinary system to be excreted in the urine. Though not common, Sh eggs can be occasionally identified in stool of infected individuals as well [218,219]. Sh could affect the fecal microbiome through the presence of eggs in the gastrointestinal tract or through a systemic effect. Ajibola et al [26] showed higher Proteobacteria and lower Firmicutes proportions in the gut microbiota by analysis of stool samples of adolescents with and without Sh infection. Furthermore, beta diversity, the measure of similarity or dissimilarity between microbiome groups, differed between people with and without Sh infection, while alpha diversity, the diversity within a microbiome, remained the same [26]. This study also emphasized how changes in the gut microbiome of adolescents with Sh infection led to a dysbiotic state. Kay et al [216] found a difference in the abundance of 5 Prevotella operational taxonomic units (OTUs) in the gut microbiome in fecal samples of children with Sh infection ages 6 months to 13 years in comparison to children without infection [216]. Osakunor et al [217] studied children with Sh infection ages 1–5 and reported that Sh infection status and intensity affects bacteria and fungi genera in stool [217]. These studies consistently demonstrate associations of Sh infection with altered microbial composition in different compartments outside of the genitourinary tract in infected adolescents and children. Changes in fecal microbiota in individuals with Sh infection may have multiple downstream consequences for the host, including altering the host’s mucosal immune system, which could impact local response to intruding pathogens as well as cancer. Furthermore, these changes in the fecal microbiota appeared to be refractory to praziquantel treatment [216,217,220].
Studying the urine microbiota in Sh infection is pertinent since the genitourinary system is the site where Sh eggs mainly become entrapped, subsequently inducing local inflammation, fibrosis, and granuloma formation [212,221]. Changes in the urine microbiome have been postulated to contribute to the pathogenesis of the development of bladder cancer in individuals with Sh infection [211,212]. Despite this, Adebayo and colleagues are the only study thus far to report urine microbial composition in individuals with Sh infection. Their study found higher Firmicutes and lower Proteobacteria proportions in the urine of individuals with Sh infection, compared to individuals without Sh infection [215]. The presence of distinct microbial species and varying levels of Firmicutes and Proteobacteria in individuals with Sh infection could induce inflammation, with less protection for the infected host. Altered Firmicutes and Proteobacteria levels have been connected to gastrointestinal dysbiosis, which can alter bile acid composition, leading to gastrointestinal tract inflammation and increased gut permeability [222–225].
Two studies investigated the cervicovaginal microbiome using swabs collected from cervicovaginal mucosa, the site of Sh egg deposition. Changes in the cervicovaginal microbiome, particularly increased diversity and loss of Lactobacilli, are associated with increased susceptibility to some infections, including HIV [226,227]. Women with high intensity Sh infections, defined as a CAA value of above 3000 pg/ ml, were found to have higher alpha diversity compared to women with lower intensity infections or women without infection [228]. After PZQ treatment, an increase in alpha diversity in participants that continued to test positive for Sh was found [228]. In contrast, Sturt et al [229] did not find differences in presence or concentration of key cervicovaginal species in women with and without FGS. Interestingly, individuals in whom two or more genital samples had detectable Sh DNA had a significantly higher risk of T. vaginalis [229]. T. vaginalis has been shown to influence HIV-1 acquisition and transmission [230,231], with some studies showing a decline in HIV-1 shedding rates after metronidazole treatment [232–234]. These two studies underscore how alterations in the cervicovaginal microbiome due to Sh infection could be a mechanism that increases host susceptibility to HIV and other infectious diseases.
Overall synthesis of microbiome studies in Sh infection
Together, the above studies demonstrate that Sh infection can lead to changes of the microbiome both locally in the genitourinary tracts where egg disposition mainly occurs, as well as in other mucosal compartments such as the gastrointestinal tract. These changes in microbial populations may have far reaching consequences on both immune responses and acquisition and transmission of diseases. To date, no study has examined the relationship between microbiota and mucosal immune populations in Sh infection, which would be an important area for future investigation.
Discussion
In this systematic and comprehensive review, a total of 89 of 94 studies (95%) demonstrated associations of Sh infection with considerable changes in the host immune response, gene expression, and/or microbiome composition (Fig 3). These changes underlie several major public health impacts of Sh infection. This chronic parasitic infection, which lasts for an average of 3–5 years when untreated [235], shifts the host’s immune phenotype to a predominate type 2 immune phenotype, provokes increases in regulatory cell populations, such as Tregs and Bregs, and inflammatory cytokines, and compromises the epithelial barrier and microbiome diversity. Each of these major changes could contribute to the impaired defenses against viruses, the increased risk of carcinogenesis, or both that are seen in Sh infection. Of further importance, the concordance of many studies that treatment with praziquantel only partially resolves these immune, gene expression, and microbial changes emphasizes the urgent need to prevent and aggressively manage this infection in the first place.
Fig 3. Changes in the host’s immune response, gene and protein expression and microbiome composition during S. haematobium infection.
Overview of the main changes in immune, gene and microbiome with S. haematobium infection reported in the 94 studies included in this review. Tregs = T regulatory cells; MBC = Memory B cells; Bregs = B regulatory cells; Th = T helper cell. Black font indicates two or more studies have demonstrated this relationship. Light grey indicates a finding that has only been reported by a single study. Image created with BioRender.com.
The studies assessed reported multiple immune alterations in Sh infection, which are summarized in Fig 4. In addition to the type 2 and regulatory phenotype mentioned above, numerous studies provided evidence that Sh infection hinders an adequate cellular immune response. This includes functional impairment of various immune cell subsets crucial for host defense against invading pathogens, such as DCs, B cell subsets, CD4+ memory, and EM T cells. Interestingly, the role of CD8+ in infection remains to be determined. One study showed no difference, while another indicated an increase in this pertinent T cell population systemically [103,123]. A number of studies also associated Sh infection with increased pro-inflammatory cytokines, such as IFN-γ, IL-6, and MIP1-α, in both blood and the genital tract [236].
Fig 4. Changes in the host’s immune system seen during S. haematobium infection.
Overview of immune changes associated with S. haematobium infection. Th = T helper cells; Tregs = T regulatory cells; Bregs = B regulatory cells; DCs = dendritic cells; ILCs = innate lymphoid cells; CVL = cervicovaginal lavage; FGS = female genital schistosomiasis. Black font indicates two or more studies have demonstrated this relationship. Light grey indicates a finding that has only been reported by a single study. Image created with BioRender.com.
When applied to the reproductive tract, where the tissue burden of Sh eggs is frequently high, these immune changes may increase the risk of acquisition and transmission of viral infections, particularly in women. It is well established that female genital tract inflammation caused by other infections creates a conducive environment for HIV acquisition, both via recruitment of HIV target cells to mucosal surfaces and via damage to epithelial integrity. Only one study in this review assessed HIV target cells in the female genital tract, and found decreases in CD4+ T cells expressing CCR5 in the genital tract following PZQ treatment [107]. Two others identified genital tract cytokine changes consistent with increased genital tract inflammation and/or decreased antiviral immunity [148,149]. It is also possible that IL-6, which one study reported to be elevated in the urinary bladder in Sh infection and which is associated with increased HIV viral shedding in the genital tract, could play a role [237].
A second putative mechanism for increased viral susceptibility in the genital tract could be Sh-induced alterations in mucosal gene expression and microbiota. The first line of host defense against pathogens is the epithelial barrier. Alterations in epithelial barrier proteins have been associated with impaired epithelial barrier function, allowing easier pathogen translocation [227,238]. In this review, many studies demonstrated lower expression of epithelial barrier proteins and higher expression of proteases, which can cause epithelial barrier destruction, in Sh infection. Interestingly, changes in the epithelial barrier can also impact the microbiome and vice-versa [239]. The reported microbial shifts associated with Sh infection, such as altered Firmicutes and Proteobacteria levels, may further inflammation. Furthermore, reported cervicovaginal findings of increased microbial diversity, abundance of taxa, and low Lactobacillus in Sh infection have all been associated with increased risk of HIV acquisition [226]. Together, these Sh infection gene expression and microbiome data corroborate and may potentiate the Sh-associated immune alterations, which collectively align with enhanced potential for increased viral susceptibility.
Of note, it has been reported that that schistosome infection might alleviate disease severity in some chronic viral infections such as HIV, HTLV-1, and respiratory viruses [29]. These observations underscore the importance of a thorough examination of immune effects of Sh infection in endemic settings where viral and Sh, as well as other helminth infections, intersect. It is possible that the mixed picture of type 2, regulatory, and pro-inflammatory immune responses in Sh infection may contribute to these sometimes seemingly paradoxical findings. Moreover, a strong Treg environment in schistosome infection has been linked to reduced hepatic damage from HBV [240], improved HTLV outcome [241] and decreased susceptibility to HIV-1 R5 virus [242]. Further research is essential to understand the reasons that underlie disparate viral presentations during Sh infection, to explore effects of Sh on other important viruses including HPV, and potentially to guide future immunoregulatory interventions that harness beneficial effects of Sh infection.
In Sh endemic countries, bladder cancer is commonly linked to past or current infections with Sh [14,158]. Across an array of human and animal studies of Sh infection, articles in this review report a Th2-skewed environment with concomitant downregulation of Th1 response, which may favor carcinogenesis. Furthermore, chronic inflammation is a well-known risk factor for the development of malignancy [243] and elements of a pro-inflammatory immune environment, in addition to type 2 findings, were identified in a substantial portion of studies included in this review. Other studies demonstrated distinctive genetic, epigenetic, protein, and cell cycle alterations in bladder cancer associated with Sh infection when compared to Sh-unassociated bladder cancer. These multiple alterations link Sh infection to an environment conducive to malignant growth. It is also possible that the noted shifts in the microbiome during Sh infection, particularly in urine, impact bladder carcinogenesis by affecting the immune response or by inducing changes in gene expression in the urothelium. Given the emerging possibility of manipulating microbiota to prevent other cancers [244], this is another important area for future research.
The variation of reported findings among the microbiome studies highlights the challenges inherent in these types of analyses. Further adding to the complexity, microbiota can impact the immune system and gene expression [245,246] and the microbiome is highly diverse, with different body sites hosting distinct microbial communities that are impacted by multiple factors, beginning from birth. The microbiome is also dynamic, with variations not only throughout the individual’s lifespan, but sometimes daily within the same individual [17,20,247]. Geographic location also impacts microbiome composition. The six microbiota-focused studies in this review investigated different compartments and spanned four different countries, with age groups ranging from 13-month-year-olds to 65-year-old adults. This could explain why the specific changes seen in one bodily compartment do not completely overlap with the findings of another study, despite investigating the same compartment. What is clear from this review is that Sh was associated with alterations in the microbiome in all three of these compartments. The scarcity of these studies highlights the need for additional microbiome analyses in Sh infection across geography, age, and assessing associations of microbiota with both baseline and provoked immune responses.
Our synthesis of articles suggests that anti-schistosome treatment results in the partial, but often incomplete, restoration of Sh-associated changes in immune phenotype, gene expression, and microbiota. The single study investigating genetic changes post- versus pre-PZQ treatment showed a reduction, but not complete normalization, of genetic alterations. The two studies investigating microbiome changes before versus three months after successful treatment did not observe any significant changes. It is possible that the microbiome may require longer time to recover after Sh infection than the three month follow up periods in these studies. Together, the study results discussed in this review argue that PZQ could be beneficial, at least in reverting some immune alterations associated with Sh infection back to a pre-infection state, but that PZQ may be less able to reverse the effects of Sh infection on gene expression and microbiota. For these reasons, it will be important to investigate whether resolution of Sh infection truly diminishes the risk of viral acquisition and the onset of bladder cancer.
This review has strengths and limitations. We included 94 studies that documented active schistosome infection by microscopy, antigen testing, PCR, serologies, or clinical exam. Serologies to diagnose Sh infection were included despite antibodies remaining positive after clearance of infection, and the possibility that some cases might not reflect active infection. Nevertheless, we included these studies which identified Sh infection based on positive serologies to ensure we did not underestimate effects of Sh infection, and in order to assess possible long-term effects of past Sh infections. The included studies assessed a broad range of human populations, sometimes leading to heterogenous results. Beyond age, sex, co-infections, and areas of residence with different Sh endemicity, a large array of other factors may influence the individual’s immune response to Sh infection. These include environmental, sociodemographic, and economic aspects of Sh infection, which could not be ascertained. Furthermore, the effects of timing, duration, and infectious burden of schistosome infection likely affect the manifestation of schistosome-associated immune, gene and microbiome changes. Finally, publication bias could have led to the non-publication of studies that showed no impact of Sh on immune system, gene expression, and microbiome and thereby would not have been included.
Despite these limitations, our rigorous analysis provides, to our knowledge, the first comprehensive synthesis of immune, genetic, and microbial factors associated with Sh infection. Our synthesis can help to guide understanding of potential supplementary therapeutic approaches to reverse consequences of Sh infection. This body of data may also pave the way for novel immunoregulatory, genetic, or microbiome interventions and guide global strategies related to prevention of infections and cancer.
Methods
We conducted a systematic review to assess the effects of Sh infection has on the immune system, gene expression and microbiome. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered prospectively in PROSPERO (CRD42022372607).
Search strategy
Comprehensive literature searches were developed and performed by a medical librarian [DW]. The initial search was performed December 22nd, 2022 via OVID MEDLINE ALL (December 22nd, 2022). The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, Technology Assessments (HTA)), LILACS (Latin American and Caribbean Health Sciences Literature), and OVID EMBASE (1974-March 28, 2019) were searched on December 22nd, 2022; Scopus (Elsevier) on December 22nd, 2022. Follow-up searches were performed on August 9th, 2023. Search terms included all subject headings and/or keywords associated with our research question, clustered as:
Parasite or proxy for parasitic infection (e.g. Schistosoma haematobium, Schistosomiasis, Bilharzia, Bilharziasis)
Immune-related headings (e.g. Immunity, Immunomodulation, Immune response, Mucosal immunity, Immune changes, Cellular immunity)
Microbiome related headings (Microbiome, Microbiota, Cervicovaginal microbiota, Genitourinary microbiota)
Gene expression-related headings (e.g. Gene expression, Mucosal gene expression, Transcriptomics)
Boolean operators ‘OR’ and ‘AND’ were used as appropriate. Grey literature and bibliographies of included articles were also searched; see full search strategy in the Supplementary Appendix (S1 Text). Publication date restrictions were not imposed. Only papers written in the English language were included. Databases were searched from inception. Authors were not contacted for further information. Studies were uploaded to the Covidence platform (Melbourne, Australia) for conduct of the screening and extraction phases. Included study types were randomized clinical trials, cohort, cross-sectional, and case-control studies. Both human, animal and experimental ex vivo studies were included. S1 Text summarizes our study’s predefined search terms, keywords, and study types included. S2 Text summarizes the decision rules for data selection and extraction.
Study selection and evaluation process
-
Study selection
After excluding duplicates, two investigators independently screened titles and abstracts to identify studies eligible for inclusion using the above criteria, and a third investigator independently resolved discrepancies. Discrepant analyses of study quality were resolved by discussion and author consensus. Due to the heterogeneity of study designs, including human, animal and ex vivo studies, a meta-analysis was not possible. We included studies describing the effects of Sh on the immune system, gene expression or microbiome. Pre-defined exclusion criteria included: not available in English, and study design of case study or case review, conference proceedings/meeting abstracts, dissertations/theses, newspaper/magazine articles and research in progress. We prespecified that studies must test for Sh infection by serologies, Sh egg detection by tissue or urine microscopy, or antigen testing. For the scope of this review, we prespecified that we would exclude studies describing humoral immune responses and solely focus on cellular immunity, cytokine and chemokine signaling and immune cell interactions. Full-text review followed the initial title and abstract screening phase, with data extracted into Microsoft Excel.
-
Data extraction
Data extracted included study type; country of origin; sample size; immunology, gene, or microbiome outcomes; key findings; effects of anthelmintic therapy on outcomes, if applicable; and study limitations.
-
Quality assessment
Quality assessment of data was performed using the Downs and Black checklist [27]. Studies were categorized as “poor,” “fair,” “good,” or “excellent” based on a summative score derived from this checklist, and only those of “fair” quality or above were included in the final analysis.
Software
The displayed graph was generated using GraphPad Prism software. Displayed figures were created with BioRender.
Supporting information
(DOCX)
(XLSX)
(DOCX)
(DOCX)
(DOCX)
Acknowledgments
We thank the librarian team at Weill Cornell Medicine for their assistance with searching and retrieving study records for this systematic review. Furthermore, we want to thank Drs. Mary Charleston and Carol Mancuso who lead the Master’s program Clinical Epidemiology & Health Services Research, and Dr. Kyu Rhee, who leads to Burroughs Wellcome Physician Scientist Program at Weill Cornell, who all have been continued supporters and offered instrumental guidance for this review.
Data Availability
All extracted data used for this systematic review are available in the tables that accompany this manuscript.
Funding Statement
This work was supported by grants for Research Training in Infectious Diseases (5T32 AI 007613; AMM) as well as K24 AI182638 (JAD) and R01 AI 168306 (JAD) from the National Institute of Allergy and Infectious Diseases, the Burroughs Wellcome Fund (BWF 1020043; AMM) and by the Fogarty International Center (D43 TW 011826; JKM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References
- 1.Colley D, Secor W. Immunology of human schistosomiasis. Parasite Immunol 2014;36:347–57. doi: 10.1111/pim.12087 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hotez P, Engels D, Gyapong M, Ducker C, Malecela M. Female Genital Schistosomiasis. N Engl J Med 2019;381:2491–3. [DOI] [PubMed] [Google Scholar]
- 3.Aula O, McManus D, Jones M, Gordon C. Schistosomiasis with a Focus on Africa. Trop Med Infect Dis 2021;6:109. doi: 10.3390/tropicalmed6030109 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.WHO. Current Estimated Total Number of Individuals with Morbidity and Mortality due to Schistosomiasis Haematobium and S. Mansoni infection in Sub-Saharan Africa. Schistosomiasis; Epidemiological situation; World Health Organisation: Pretoria, South Africa. 2020. https://www.who.int/teams/control-of-neglected-tropical-diseases/schistosomiasis/epidemiology (accessed December 9, 2023).
- 5.Wang H, Naghavi M, Allen C, Barber R, Bhutta Z, Carter A, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet 2016;388:1459–544. doi: 10.1016/S0140-6736(16)31012-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Downs J, Mguta C, Kaatano G, Mitchell K, Bang H, Simplice H, et al. Urogenital Schistosomiasis in Women of Reproductive Age in Tanzania’s Lake Victoria Region. Am J Trop Med Hyg 2011;84:364–9. doi: 10.4269/ajtmh.2011.10-0585 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gadoth A, Mvumbi G, Hoff N, Musene K, Mukadi P, Ashbaugh H, et al. Urogenital Schistosomiasis and Sexually Transmitted Coinfections among Pregnant Women in a Schistosome-Endemic Region of the Democratic Republic of Congo. Am J Trop Med Hyg 2019;101:828–36. doi: 10.4269/ajtmh.19-0024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wall K, Kilembe W, Vwalika B, Dinh C, Livingston P, Lee Y, et al. Schistosomiasis is associated with incident HIV transmission and death in Zambia. PLoS Negl Trop Dis 2018;12:e0006902. doi: 10.1371/journal.pntd.0006902 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kjetland E, Ndhlovu P, Gomo E, Mduluza T, Midzi N, Gwanzura L, et al. Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS 2006;20:593–600. doi: 10.1097/01.aids.0000210614.45212.0a [DOI] [PubMed] [Google Scholar]
- 10.Furch B, Koethe J, Kayamba V, Heimburger D, Kelly P. Interactions of Schistosoma and HIV in Sub-Saharan Africa: A Systematic Review. Am J Trop Med Hyg 2020;102:711–8. doi: 10.4269/ajtmh.19-0494 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kjetland E, Ndhlovu P, Mduluza T, Deschoolmeester V, Midzi N, Gomo E, et al. The effects of genital schistosoma haematobium on human papillomavirus and the development of cervical neoplasia after five years in a Zimbabwean population. Eur J Gynaecol Oncol 2010;31:169–73. [PubMed] [Google Scholar]
- 12.Downs J, Dupnik K, van Dam G, Urassa M, Lutonja P, Kornelis D, et al. Effects of schistosomiasis on susceptibility to HIV-1 infection and HIV-1 viral load at HIV-1 seroconversion: A nested case-control study. PLoS Negl Trop Dis 2017;11:e0005968. doi: 10.1371/journal.pntd.0005968 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Nalugwa A, Nuwaha F, Tukahebwa E, Olsen A. Single Versus Double Dose Praziquantel Comparison on Efficacy and Schistosoma mansoni Re-Infection in Preschool-Age Children in Uganda: A Randomized Controlled Trial. PLoS Negl Trop Dis 2015;9:e0003796. doi: 10.1371/journal.pntd.0003796 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Zaghloul M. Bladder cancer and schistosomiasis. J Egypt Natl Cancer Inst 2012;24:151–9. doi: 10.1016/j.jnci.2012.08.002 [DOI] [PubMed] [Google Scholar]
- 15.Zarzour A, Selim M, Abd-Elsayed A, Hameed D, AbdelAziz M. Muscle invasive bladder cancer in Upper Egypt: the shift in risk factors and tumor characteristics. BMC Cancer 2008;8:250. doi: 10.1186/1471-2407-8-250 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zheng Y, Amr S, Saleh D, Dash C, Ezzat S, Mikhail N, et al. Urinary bladder cancer risk factors in Egypt: a multi-center case-control study. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 2012;21:537–46. doi: 10.1158/1055-9965.EPI-11-0589 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cho I, Blaser M. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13:260–70. doi: 10.1038/nrg3182 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Jernberg C, Löfmark S, Edlund C, Jansson J. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiol Read Engl 2010;156:3216–23. doi: 10.1099/mic.0.040618-0 [DOI] [PubMed] [Google Scholar]
- 19.Dominguez-Bello MG, Blaser M, Ley R, Knight R. Development of the Human Gastrointestinal Microbiota and Insights From High-Throughput Sequencing. Gastroenterology 2011;140:1713–9. doi: 10.1053/j.gastro.2011.02.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Greenhalgh K, Meyer K, Aagaard K, Wilmes P. The human gut microbiome in health: establishment and resilience of microbiota over a lifetime. Environ Microbiol 2016;18:2103–16. doi: 10.1111/1462-2920.13318 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Blanton L, Charbonneau M, Salih T, Barratt M, Venkatesh S, Ilkaveya O, et al. Gut bacteria that rescue growth impairments transmitted by immature microbiota from undernourished children. Science 2016;351: aad3311. doi: 10.1126/science.aad3311 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sonnenburg J, Sonnenburg E. Vulnerability of the industrialized microbiota. Science 2019;366:eaaw9255. doi: 10.1126/science.aaw9255 [DOI] [PubMed] [Google Scholar]
- 23.Tamburini F, Maghini D, Oduaran O, Brewster R, Hulley M, Sahibdeen V, et al. Short- and long-read metagenomics of urban and rural South African gut microbiomes reveal a transitional composition and undescribed taxa. Nat Commun 2022;13:926. doi: 10.1038/s41467-021-27917-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Seo D, Holtzman D. Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci 2020;75:1232–41. doi: 10.1093/gerona/glz262 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Mishra P, Palma M, Bleich D, Loke P, Gause W. Systemic impact of intestinal helminth infections. Mucosal Immunol 2014;7:753–62. doi: 10.1038/mi.2014.23 [DOI] [PubMed] [Google Scholar]
- 26.Ajibola O, Rowan A, Ogedengbe C, Mshelia M, Cabral D, Eze A, et al. Urogenital schistosomiasis is associated with signatures of microbiome dysbiosis in Nigerian adolescents. Sci Rep 2019;9:829. doi: 10.1038/s41598-018-36709-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Downs S, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;52:377–84. doi: 10.1136/jech.52.6.377 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Odegaard J, Hsieh M. Immune responses to Schistosoma haematobium infection. Parasite Immunol 2014;36:428–38. doi: 10.1111/pim.12084 [DOI] [PubMed] [Google Scholar]
- 29.Bullington B, Klemperer K, Mages K, Chalem A, Mazigo H, Changalucha J, et al. Effects of schistosomes on host anti-viral immune response and the acquisition, virulence, and prevention of viral infections: A systematic review. PLOS Pathog 2021;17:e1009555. doi: 10.1371/journal.ppat.1009555 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Ishida K, Hsieh H. Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update. Front Med 2018;5:223. doi: 10.3389/fmed.2018.00223 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Gause W, Wynn T, Allen J. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 2013;13:607–14. doi: 10.1038/nri3476 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Pearce P, Caspar P, Grzych J, Lewis F, Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med 1991;173:159–66. doi: 10.1084/jem.173.1.159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Chetty A, Omondi M, Butters C, Smith K, Katawa G, Ritter M, et al. Impact of Helminth Infections on Female Reproductive Health and Associated Diseases. Front Immunol 2020;11:577516. doi: 10.3389/fimmu.2020.577516 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Abdel Aziz N, Musaigwa F, Mosala P, Berkiks I, Brombacher F. Type 2 immunity: a two-edged sword in schistosomiasis immunopathology. Trends Immunol 2022;43:657–73. doi: 10.1016/j.it.2022.06.005 [DOI] [PubMed] [Google Scholar]
- 35.Hotez PJ, Harrison W, Fenwick A, Bustinduy AL, Ducker C, Mbabazi PS, et al. Female genital schistosomiasis and HIV/AIDS: Reversing the neglect of girls and women. PLoS Negl Trop Dis 2019;13:e0007025. doi: 10.1371/journal.pntd.0007025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther 2023;8:1–50. doi: 10.1038/s41392-023-01471-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Zhu J, Yamane H, Paul W. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010;28:445–89. doi: 10.1146/annurev-immunol-030409-101212 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.van Loo G, Bertrand M. Death by TNF: a road to inflammation. Nat Rev Immunol 2023;23:289–303. doi: 10.1038/s41577-022-00792-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Jang D, Lee A, Shin H, Song H, Park J, Kang T, et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol Sci 2021;22:2719. doi: 10.3390/ijms22052719 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Paul W, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol 2010;10:225–35. doi: 10.1038/nri2735 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Walker J, McKenzie A. TH2 cell development and function. Nat Rev Immunol 2019;18:121–33. doi: 10.1038/nri.2017.118 [DOI] [PubMed] [Google Scholar]
- 42.Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 2012;12:180–90. doi: 10.1038/nri3156 [DOI] [PubMed] [Google Scholar]
- 43.Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med 2007;204:239–43. doi: 10.1084/jem.20070104 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Benveniste EN, Kwon J, Chung W, Sampson J, Pandya K, Tang LP. Differential modulation of astrocyte cytokine gene expression by TGF-beta. J Immunol 1994;153:5210–21. doi: 10.4049/jimmunol.153.11.5210 [DOI] [PubMed] [Google Scholar]
- 45.Chaudhury A, Howe P. The Tale of Transforming Growth Factor-β (TGFβ) Signaling: A Soigné Enigma. IUBMB Life 2009;61:929–39. doi: 10.1002/iub.239 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen 2019;39:12. doi: 10.1186/s41232-019-0101-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Rose-John S, Winthrop K, Calabrese L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol 2017;13:399–409. doi: 10.1038/nrrheum.2017.83 [DOI] [PubMed] [Google Scholar]
- 48.Fehniger T, Caligiuri M. Interleukin 15: biology and relevance to human disease. Blood 2001;97:14–32. doi: 10.1182/blood.v97.1.14 [DOI] [PubMed] [Google Scholar]
- 49.Ihim S, Abubakar S, Zian Z, Sasaki T, Saffarioun M, Maleknia S, et al. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front Immunol 2022;13. doi: 10.3389/fimmu.2022.919973 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol 2023;23:38–54. doi: 10.1038/s41577-022-00746-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Zambrano-Zaragoza J, Romo-Martínez E, Durán-Avelar M, García-Magallanes N, Vibanco-Pérez N. Th17 Cells in Autoimmune and Infectious Diseases. Int J Inflamm 2014;2014:651503. doi: 10.1155/2014/651503 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Guglani L, Khader S. Th17 cytokines in mucosal immunity and inflammation. Curr Opin HIV AIDS 2010;5:120–7. doi: 10.1097/COH.0b013e328335c2f6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Spolski R, Leonard W. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 2014;13:379–95. doi: 10.1038/nrd4296 [DOI] [PubMed] [Google Scholar]
- 54.Teng M, Bowman E, McElwee J, Smyth M, Casanova A, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015;21:719–29. doi: 10.1038/nm.3895 [DOI] [PubMed] [Google Scholar]
- 55.Deshmane S, Kremlev S, Amini S, Sawaya B. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. J Interferon Cytokine Res 2009;29:313–26. doi: 10.1089/jir.2008.0027 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Ben-Baruch A, Xu L, Young P, Bengali K, Oppenheim J, Wang J. Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors. C-C CKR1, a receptor for macrophage inflammatory protein-1 alpha/Rantes, is also a functional receptor for MCP3. J Biol Chem 1995;270:22123–8. doi: 10.1074/jbc.270.38.22123 [DOI] [PubMed] [Google Scholar]
- 57.Mduluza T, Ndhlovu P, Midzi N, Mary C, Paris C, Turner C, et al. T cell clones from Schistosoma haematobium infected and exposed individuals lacking distinct cytokine profiles for Th1/Th2 polarisation. Mem Inst Oswaldo Cruz 2001;96:89–101. doi: 10.1590/s0074-02762001000900013 [DOI] [PubMed] [Google Scholar]
- 58.Labuda L, Adegnika A, Rosa B, Martin J, Ateba-Ngoa U, Amoah A, et al. A Praziquantel Treatment Study of Immune and Transcriptome Profiles in Schistosoma haematobium -Infected Gabonese Schoolchildren. J Infect Dis 2020;222:2103–13. doi: 10.1093/infdis/jiz641 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Lyke K, Dabo A, Sangare L, Arama C, Daou M, Diarra I, et al. Effects of concomitant Schistosoma haematobium infection on the serum cytokine levels elicited by acute Plasmodium falciparum malaria infection in Malian children. Infect Immun 2006;74:5718–24. doi: 10.1128/IAI.01822-05 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Ateba-Ngoa U, Adegnika A, Zinsou J, Kassa Kassa R, Smits H, Massinga-Loembe M, et al. Cytokine and chemokine profile of the innate and adaptive immune response of Schistosoma haematobium and Plasmodium falciparum single and co-infected school-aged children from an endemic area of Lambaréné, Gabon. Malar J 2015;14:94. doi: 10.1186/s12936-015-0608-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Imai N, Rujeni N, Nausch N, Bourke C, Appleby L, Cowan G, et al. Exposure, infection, systemic cytokine levels and antibody responses in young children concurrently exposed to schistosomiasis and malaria. Parasitology 2011;138:1519–33. doi: 10.1017/S0031182011001181 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Van Der Kleij D, Van Den Biggelaar A, Kruize Y, Retra K, Fillie Y, Schmitz M, et al. Responses to Toll-Like Receptor Ligands in Children Living in Areas Where Schistosome Infections Are Endemic. J Infect Dis 2004;189:1044–51. doi: 10.1086/382089 [DOI] [PubMed] [Google Scholar]
- 63.Meurs L, Labuda L, Amoah A, Mbow M, Ngoa U, Boakye D, et al. Enhanced pro-inflammatory cytokine responses following Toll-like-receptor ligation in Schistosoma haematobium-infected schoolchildren from rural Gabon. PloS One 2011;6:e24393. doi: 10.1371/journal.pone.0024393 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Antony J, Ojurongbe O, Meyer C, Thangaraj K, Mishra A, Kremsner P, et al. Correlation of Interleukin-6 levels and lectins during Schistosoma haematobium infection. Cytokine 2015;76:152–5. doi: 10.1016/j.cyto.2015.04.019 [DOI] [PubMed] [Google Scholar]
- 65.Bustinduy A, Sutherland L, Chang-Cojulun A, Malhotra I, DuVall A, Fairley J, et al. Age-Stratified Profiles of Serum IL-6, IL-10, and TNF-α Cytokines among Kenyan Children with Schistosoma haematobium, Plasmodium falciparum, and Other Chronic Parasitic Co-infections. Am J Trop Med Hyg 2015;92:945–51. doi: 10.4269/ajtmh.14-0444 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Kasambala M, Mukaratirwa S, Vengesai A, Mduluza-Jokonya T, Jokonya L, Midzi H, et al. The association of systemic inflammation and cognitive functions of pre-school aged children residing in a Schistosoma haematobium endemic area in Zimbabwe. Front Immunol 2023;14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Njaanake K, Simonsen P, Vennervald B, Mukoko D, Reimert C, Gachuhi K, et al. Urinary cytokines in Schistosoma haematobium-infected schoolchildren from Tana Delta District of Kenya. BMC Infect Dis 2014;14:501. doi: 10.1186/1471-2334-14-501 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Grogan J, Kremsner P, Deelder A, Yazdanbakhsh M. The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells. Parasite Immunol 1998;20:345–9. doi: 10.1046/j.1365-3024.1998.00157.x [DOI] [PubMed] [Google Scholar]
- 69.King C, Medhat A, Malhotra I, Nafeh M, Helmy A, Khaudary J, et al. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J Immunol 1996;156:4715–21. doi: 10.4049/jimmunol.156.12.4715 [DOI] [PubMed] [Google Scholar]
- 70.Mutapi F, Winborn G, Midzi N, Taylor M, Mduluza T, Maizels R. Cytokine responses to Schistosoma haematobium in a Zimbabwean population: contrasting profiles for IFN-γ, IL-4, IL-5 and IL-10 with age. BMC Infect Dis 2007;7:139. doi: 10.1186/1471-2334-7-139 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Mutapi F, Imai N, Nausch N, Bourke C, Rujeni N, Mitchell K, et al. Schistosome infection intensity is inversely related to auto-reactive antibody levels. PloS One 2001;6:e19149. doi: 10.1371/journal.pone.0019149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Milner T, Reilly L, Nausch N, Midzi N, Mduluza T, Maizels R, et al. Circulating cytokine levels and antibody responses to human Schistosoma haematobium: IL-5 and IL-10 levels depend upon age and infection status. Parasite Immunol 2010;32:710–21. doi: 10.1111/j.1365-3024.2010.01235.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Colombe S, Lee M, Masikini P, van Lieshout L, de Dood C, Hoekstra P, et al. Decreased Sensitivity of Schistosoma sp. Egg Microscopy in Women and HIV-Infected Individuals. Am J Trop Med Hyg 2018;98:1159–64. doi: 10.4269/ajtmh.17-0790 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.King C, Malhotra I, Mungai P, Wamachi A, Kioko J, Muchiri E, et al. Schistosoma haematobium—Induced Urinary Tract Morbidity Correlates with Increased Tumor Necrosis Factor–α and Diminished Interleukin-10 Production. J Infect Dis 2001;184:1176–82. doi: 10.1086/323802 [DOI] [PubMed] [Google Scholar]
- 75.Grogan J, Kremsner PG, Deelder A, Yazdanbakhsh M. Antigen-Specific Proliferation and Interferon-g and Interleukin-5 Production Are Down-Regulated during Schistosoma haematobium Infection. J Infect 1998;177:1433–7. [DOI] [PubMed] [Google Scholar]
- 76.Klein S, Flanagan K. Sex differences in immune responses. Nat Rev Immunol 2016;16:626–38. doi: 10.1038/nri.2016.90 [DOI] [PubMed] [Google Scholar]
- 77.Taneja V. Sex Hormones Determine Immune Response. Front Immunol 2018;9:1931. doi: 10.3389/fimmu.2018.01931 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Monin L, Whettlock E, Male V. Immune responses in the human female reproductive tract. Immunology 2020;160:106–15. doi: 10.1111/imm.13136 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Morrison C, Fichorova R, Mauck C, Chen P, Kwok C, Chipato R, et al. Cervical Inflammation and Immunity Associated With Hormonal Contraception, Pregnancy, and HIV-1 Seroconversion. JAIDS J Acquir Immune Defic Syndr 2014;66:109–17. doi: 10.1097/QAI.0000000000000103 [DOI] [PubMed] [Google Scholar]
- 80.Wira C, Rodriguez-Garcia M, Patel M. The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol 2015;15:217–30. doi: 10.1038/nri3819 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Flynn L, Byrne B, Carton J, O’Farrelly C, Kelehan P, O’Herlihy C. Menstrual Cycle Dependent Fluctuations in NK and T-Lymphocyte Subsets from Non-Pregnant Human Endometrium: ENDOMETRIAL LYMPHOCYTES DURING THE MENSTRUAL CYCLE. Am J Reprod Immunol 2000;43:209–17. doi: 10.1111/j.8755-8920.2000.430405.x [DOI] [PubMed] [Google Scholar]
- 82.Doisne J, Balmas E, Boulenouar S, Gaynor L, Kieckbusch J, Gardner L, et al. Composition, Development, and Function of Uterine Innate Lymphoid Cells. J Immunol Author Choice 2015;195:3937–45. doi: 10.4049/jimmunol.1500689 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Remoué F, To Van D, Schacht A-M, Picquet M, Garraud O, Vercruysse J, et al. Gender-dependent specific immune response during chronic human Schistosomiasis haematobia. Clin Exp Immunol 2001;124:62–8. doi: 10.1046/j.1365-2249.2001.01495.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Wilson S, Jones F, Fofana H, Landouré A, Kimani G, Mwatha J, et al. A late IL-33 response after exposure to Schistosoma haematobium antigen is associated with an up-regulation of IL-13 in human eosinophils. Parasite Immunol 2013;35:224–8. doi: 10.1111/pim.12035 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Wilson S, Jones F, Fofana H, Doucouré A, Landouré A, Kimani G, et al. Rapidly boosted Plasma IL-5 induced by treatment of human Schistosomiasis haematobium is dependent on antigen dose, IgE and eosinophils. PLoS Negl Trop Dis 2013;7:e2149. doi: 10.1371/journal.pntd.0002149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Fitzsimmons C, Jones F, Pinot de Moira A, Protasio A, Khalife J, Dickinson H, et al. Progressive Cross-Reactivity in IgE Responses: an Explanation for the Slow Development of Human Immunity to Schistosomiasis? Infect Immun 2012;80:4264–70. doi: 10.1128/IAI.00641-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Bourke C, Nausch N, Rujeni N, Appleby L, Mitchell K, Midzi N, et al. Integrated analysis of innate, Th1, Th2, Th17, and regulatory cytokines identifies changes in immune polarisation following treatment of human schistosomiasis. J Infect Dis 2013;208:159–69. doi: 10.1093/infdis/jis524 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Mduluza T, Ndhlovu P, Midzi N, Scott J, Mutapi F, Mary C, et al. Contrasting cellular responses in Schistosoma haematobium infected and exposed individuals from areas of high and low transmission in Zimbabwe. Immunol Lett 2003;88:249–56. doi: 10.1016/s0165-2478(03)00088-9 [DOI] [PubMed] [Google Scholar]
- 89.Zinyama-Gutsire R, Gomo E, Kallestrup P, Erikstrup C, Ullum H, Butterworth A, et al. Downregulation of MIP-1α/CCL3 with praziquantel treatment in Schistosoma haematobiumand HIV-1 co-infected individuals in a rural community in Zimbabwe. BMC Infect Dis 2009;9:174. doi: 10.1186/1471-2334-9-174 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90.Griffin GE, Leung K, Folks TM, Kunkel S, Nabel GJ. Induction of NF-×B during monocyte differentiation is associated with activation of HIV-gene expression n.d. [DOI] [PubMed] [Google Scholar]
- 91.Medhat A, Shehata M, Bucci K, Mohamed S, Dief A, Badary S, et al. Increased Interleukin-4 and Interleukin-5 Production in Response to Schistosoma haematobium Adult Worm Antigens Correlates with Lack of Reinfection after Treatment. J Infect Dis 1998;178:512–9. doi: 10.1086/515630 [DOI] [PubMed] [Google Scholar]
- 92.Khalil H, Abd el Baki M, Abd el Mawla M, Maklad K, Sharaf S, Saad A. Interleukin-4, immunoglobulin E and immunoglobulin A and resistance to re-infection with Schistosoma haematobium before and after chemotherapy. J Egypt Soc Parasitol 1999;29:395–408. [PubMed] [Google Scholar]
- 93.van den Biggelaar A, Borrmann S, Kremsner P, Yazdanbakhsh M. Immune Responses Induced by Repeated Treatment Do Not Result in Protective Immunity to Schistosoma haematobium: Interleukin (IL)-5 and IL-10 Responses. J Infect Dis 2002;186:1474–82. doi: 10.1086/344352 [DOI] [PubMed] [Google Scholar]
- 94.Pearce E, MacDonald A. The immunobiology of schistosomiasis. Nat Rev Immunol 2002;2:499–511. doi: 10.1038/nri843 [DOI] [PubMed] [Google Scholar]
- 95.Molehin A. Current Understanding of Immunity Against Schistosomiasis: Impact on Vaccine and Drug Development. Res Rep Trop Med 2020;11:119–28. doi: 10.2147/RRTM.S274518 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Ross M, Blair D, Weber M, Gelfand M. Distribution and Extent of Schistosomiasis in Female Pelvic Organs, with Special Reference to the Genital Tract, as Determined at Autopsy. Am J Trop Med Hyg 1971;20:846–9. doi: 10.4269/ajtmh.1971.20.846 [DOI] [PubMed] [Google Scholar]
- 97.Kubach J, Becker C, Schmitt E, Steinbrink K, Huter E, Tuettenberg A, et al. Dendritic Cells: Sentinels of Immunity and Tolerance. Int J Hematol 2005;81:197–203. doi: 10.1532/IJH97.04165 [DOI] [PubMed] [Google Scholar]
- 98.Sousa C. Dendritic Cells as Sensors of Infection. Immunity 2001;14:495–8. doi: 10.1016/s1074-7613(01)00136-4 [DOI] [PubMed] [Google Scholar]
- 99.Robinson S, Patterson S, English N, Davies D, Knight S, Reid C. Human peripheral blood contains two distinct lineages of dendritic cells. Eur J Immunol 1999;29:2769–78. doi: [DOI] [PubMed] [Google Scholar]
- 100.Liu Y. Dendritic Cell Subsets and Lineages, and Their Functions in Innate and Adaptive Immunity. Cell 2001;106:259–62. doi: 10.1016/s0092-8674(01)00456-1 [DOI] [PubMed] [Google Scholar]
- 101.Kadowaki N. Dendritic Cells—A Conductor of T Cell Differentiation—. Allergol Int 2007;56:193–9. doi: 10.2332/allergolint.R-07-146 [DOI] [PubMed] [Google Scholar]
- 102.Everts B, Adegnika A, Kruize Y, Smits H, Kremsner P, Yazdanbakhsh M. Functional Impairment of Human Myeloid Dendritic Cells during Schistosoma haematobium Infection. PLoS Negl Trop Dis 2010;4:e667. doi: 10.1371/journal.pntd.0000667 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Nausch N, Louis D, Lantz O, Peguillet I, Trottein F, Chen IYD, et al. Age-Related Patterns in Human Myeloid Dendritic Cell Populations in People Exposed to Schistosoma haematobium Infection. PLoS Negl Trop Dis 2012;6:e1824. doi: 10.1371/journal.pntd.0001824 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, et al. Immune Response in Mice that Lack the Interferon-γ Receptor. Science 1993;259:1742–5. doi: 10.1126/science.8456301 [DOI] [PubMed] [Google Scholar]
- 105.van de Winkel JGJ, Capel PJA. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol Today 1993;14:215–21. doi: 10.1016/0167-5699(93)90166-I [DOI] [PubMed] [Google Scholar]
- 106.Gessner J, Heiken H, Tamm A, Schmidt R. The IgG Fc receptor family. Ann Hematol 1998;76:231–48. doi: 10.1007/s002770050396 [DOI] [PubMed] [Google Scholar]
- 107.Kleppa E, Ramsuran V, Zulu S, Karlsen G, Bere A, Passmore J, et al. Effect of Female Genital Schistosomiasis and Anti-Schistosomal Treatment on Monocytes, CD4+ T-Cells and CCR5 Expression in the Female Genital Tract. PLOS ONE 2014;9:e98593. doi: 10.1371/journal.pone.0098593 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Appleby L, Nausch N, Erskine L, Bourke C, Rujeni N, Midzi N, et al. CD16 Expression on Monocytes in Healthy Individuals but Not Schistosome-Infected Patients Is Positively Associated with Levels of Parasite-Specific IgG and IgG1. PLoS Negl Trop Dis 2014;8:e3049. doi: 10.1371/journal.pntd.0003049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Mutapi F, Ndhlovu P, Hagan P, Woolhouse M. A comparison of humoral responses to Schistosoma haematobium in areas with low and high levels of infection. Parasite Immunol 1997;19:255–63. doi: 10.1046/j.1365-3024.1997.d01-206.x [DOI] [PubMed] [Google Scholar]
- 110.Mutapi F, Mduluza T, Gomez-Escobar N, Gregory W, Fernandez C, Midzi N, et al. Immuno-epidemiology of human Schistosoma haematobium infection: preferential IgG3 antibody responsiveness to a recombinant antigen dependent on age and parasite burden. BMC Infect Dis 2006;6:1–11. doi: 10.1186/1471-2334-6-96 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Huang L, Appleton J. Eosinophils in Helminth Infection: Defenders and Dupes. Trends Parasitol 2016;32:798–807. doi: 10.1016/j.pt.2016.05.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Verwaerde C, Joseph M, Capron M, Pierce RJ, Damonneville M, Velge F, et al. Functional properties of a rat monoclonal IgE antibody specific for Schistosoma mansoni. J Immunol 1987;138:4441–6. doi: 10.4049/jimmunol.138.12.4441 [DOI] [PubMed] [Google Scholar]
- 113.Mbow M, Larkin B, Meurs L, Wammes L, De Jong S, Labuda L, et al. T-Helper 17 Cells Are Associated With Pathology in Human Schistosomiasis. J Infect Dis 2013;207:186–95. doi: 10.1093/infdis/jis654 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Hagan P, Wilkins H, Blumenthal U, Hayes R, Greenwood B. Eosinophilia and resistance to Schistosoma haematobium in man. Parasite Immunol 1985;7:625–32. doi: 10.1111/j.1365-3024.1985.tb00106.x [DOI] [PubMed] [Google Scholar]
- 115.Eberl G, Di Santo J, Vivier E. The brave new world of innate lymphoid cells. Nat Immunol 2015;16:1–5. doi: 10.1038/ni.3059 [DOI] [PubMed] [Google Scholar]
- 116.Sonnenberg GF, Mjösberg J, Spits H, Artis D. SnapShot: Innate Lymphoid Cells. Immunity 2012;39:622–622.e1. doi: 10.1016/j.immuni.2013.08.021 [DOI] [PubMed] [Google Scholar]
- 117.Nausch N, Appleby L, Sparks A, Midzi N, Mduluza T, Mutapi F. Group 2 Innate Lymphoid Cell Proportions Are Diminished in Young Helminth Infected Children and Restored by Curative Anti-helminthic Treatment. PLoS Negl Trop Dis 2015;9:e0003627. doi: 10.1371/journal.pntd.0003627 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Feldmeier H, Kern P, Niel G. Modulation of in vitro lymphocyte proliferation in patients with Schistosomiasis haematobium, Schistosomiasis mansoni and mixed infections. Tropenmed Parasit 1981;32:237–42. [PubMed] [Google Scholar]
- 119.Schmiedel Y, Mombo-Ngoma G, Labuda L, Janse J, de Gier B, Adegnika A, et al. CD4+CD25hiFOXP3+ Regulatory T Cells and Cytokine Responses in Human Schistosomiasis before and after Treatment with Praziquantel. PLoS Negl Trop Dis 2015;9:e0003995. doi: 10.1371/journal.pntd.0003995 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Kaech S, Wherry E. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 2007;27:393–405. doi: 10.1016/j.immuni.2007.08.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Kaech S, Wherry E, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002;2:251–62. doi: 10.1038/nri778 [DOI] [PubMed] [Google Scholar]
- 122.Gray J, Westerhof L, MacLeod MKL. The roles of resident, central and effector memory CD4 T-cells in protective immunity following infection or vaccination. Immunology 2018;154:574–81. doi: 10.1111/imm.12929 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Nmorsi O, Ukwandu N, Egwungenya O, Obhiemi N. Evaluation of CD4+/CD8+ status and urinary tract infections associated with urinary schistosomiasis among some rural Nigerians. Afr Health Sci 2005;5:126–30. [PMC free article] [PubMed] [Google Scholar]
- 124.Kleppa E, Klinge K, Galaphaththi-Arachchige H, Holmen S, Lillebø K, Onsrud M, et al. Schistosoma haematobium Infection and CD4+ T-Cell Levels: A Cross-Sectional Study of Young South African Women. PLOS ONE 2015;10:e0119326. doi: 10.1371/journal.pone.0119326 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125.Kroidl I, Chachage M, Mnkai J, Nsojo A, Berninghoff M, Verweij JJ, et al. Wuchereria bancrofti infection is linked to systemic activation of CD4 and CD8 T cells. PLoS Negl Trop Dis 2019;13:e0007623. doi: 10.1371/journal.pntd.0007623 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Nausch N, Bourke C, Appleby L, Rujeni N, Lantz O, Trottein F, et al. Proportions of CD4+ memory T cells are altered in individuals chronically infected with Schistosoma haematobium. Sci Rep 2012;2:472. doi: 10.1038/srep00472 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Grogan J, Kremsner P, Deelder A, Yazdanbakhsh M. Elevated proliferation and interleukin-4 release from CD4+ cells after chemotherapy in human Schistosoma haematobium infection. Eur J Immunol 1996;26:1365–70. doi: 10.1002/eji.1830260628 [DOI] [PubMed] [Google Scholar]
- 128.DiNardo A, Nishiguchi T, Mace E, Rajapakshe K, Mtetwa G, Kay A, et al. Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes. J Immunol 2018;201:124–33. doi: 10.4049/jimmunol.1800101 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Wang B, Liang S, Wang Y, Zhu X, Gong W, Zhang H, et al. Th17 Down-regulation Is Involved in Reduced Progression of Schistosomiasis Fibrosis in ICOSL KO Mice. PLoS Negl Trop Dis 2015;9:e0003434. doi: 10.1371/journal.pntd.0003434 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Chen D, Luo X, Xie H, Gao Z, Fang H, Huang J. Characteristics of IL-17 induction by Schistosoma japonicum infection in C57BL/6 mouse liver. Immunology 2013;139:523–32. doi: 10.1111/imm.12105 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Kalantari P, Bunnell S, Stadecker M. The C-type Lectin Receptor-Driven, Th17 Cell-Mediated Severe Pathology in Schistosomiasis: Not All Immune Responses to Helminth Parasites Are Th2 Dominated. Front Immunol 2019;10:26. doi: 10.3389/fimmu.2019.00026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132.Nausch N, Midzi N, Mduluza T, Maizels RM, Mutapi F. Regulatory and Activated T Cells in Human Schistosoma haematobium Infections. PLoS ONE 2011;6:e16860. doi: 10.1371/journal.pone.0016860 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Mihrshahi R, Barclay AN, Brown MH. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J Immunol Baltim Md 1950 2009;183:4879–86. doi: 10.4049/jimmunol.0901531 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Caserta S, Nausch N, Sawtell A, Drummond R, Barr T, MacDonald S, et al. Chronic Infection Drives Expression of the Inhibitory Receptor CD200R, and Its Ligand CD200, by Mouse and Human CD4 T Cells. PLOS ONE 2012;7:e35466. doi: 10.1371/journal.pone.0035466 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Zea A, Rodriguez P, Culotta K, Hernandez C, DeSalvo J, Ochoa J, et al. l-Arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes. Cell Immunol 2004;232:21–31. doi: 10.1016/j.cellimm.2005.01.004 [DOI] [PubMed] [Google Scholar]
- 136.Appleby L, Nausch N, Bourke C, Mutapi F, Midzi N, Mduluza T, et al. Down regulation of the TCR complex CD3 ζ-chain on CD3+ T cells: a potential mechanism for helminth mediated immune modulation. Front Immunol 2015;6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Feldmeier H, Krantz I, Poggensee G. Female genital schistosomiasis as a risk-factor for the transmission of HIV. Int J STD AIDS 1994;5:368–72. doi: 10.1177/095646249400500517 [DOI] [PubMed] [Google Scholar]
- 138.Lyke K, Wang A, Dabo A, Arama C, Daou M, Diarra I, et al. Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-Infected Malian Children. PLOS ONE 2012;7:e37868. doi: 10.1371/journal.pone.0037868 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.Labuda L, Ateba-Ngoa U, Feugap E, Heeringa J, van der Vlugt L, Pires R, et al. Alterations in Peripheral Blood B Cell Subsets and Dynamics of B Cell Responses during Human Schistosomiasis. PLoS Negl Trop Dis 2013;7:e2094. doi: 10.1371/journal.pntd.0002094 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140.Rujeni N, Nausch N, Midzi N, Gwisai R, Mduluza T, Taylor D, et al. Soluble CD23 Levels are Inversely Associated with Atopy and Parasite-Specific IgE Levels but Not with Polyclonal IgE Levels in People Exposed to Helminth Infection. Int Arch Allergy Immunol 2013;161:333–41. doi: 10.1159/000346545 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.van der Vlugt L, Labuda L, Ozir-Fazalalikhan A, Lievers E, Gloudemans A, Liu K, et al. Schistosomes Induce Regulatory Features in Human and Mouse CD1dhi B Cells: Inhibition of Allergic Inflammation by IL-10 and Regulatory T Cells. PLOS ONE 2012;7:e30883. doi: 10.1371/journal.pone.0030883 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.van der Vlugt L, Zinsou J, Ozir-Fazalalikhan A, Kremsner P, Yazdanbakhsh M, Adegnika A, et al. Interleukin 10 (IL-10)-producing CD1dhi regulatory B cells from Schistosoma haematobium-infected individuals induce IL-10-positive T cells and suppress effector T-cell cytokines. J Infect Dis 2014;210:1207–16. doi: 10.1093/infdis/jiu257 [DOI] [PubMed] [Google Scholar]
- 143.Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman D. Lipopolysaccharide-Activated B Cells Down-Regulate Th1 Immunity and Prevent Autoimmune Diabetes in Nonobese Diabetic Mice. J Immunol 2001;167:1081–9. doi: 10.4049/jimmunol.167.2.1081 [DOI] [PubMed] [Google Scholar]
- 144.Siewe B, Stapleton J, Martinson J, Keshavarzian A, Kazmi N, Demarais P, et al. Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+ T cell function in vitro. J Leukoc Biol 2013;93:811–8. doi: 10.1189/jlb.0912436 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Sugalski J, Rodriguez B, Moir S, Anthony D. Peripheral Blood B Cell Subset Skewing Is Associated with Altered Cell Cycling and Intrinsic Resistance to Apoptosis and Reflects a State of Immune Activation in Chronic Hepatitis C Virus Infection. J Immunol Baltim Md 1950 2010;185:3019–27. doi: 10.4049/jimmunol.1000879 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Kayuni S, Lampiao F, Makaula P, Juziwelo L, Lacourse E, Reinhard-Rupp J, et al. A systematic review with epidemiological update of male genital schistosomiasis (MGS): A call for integrated case management across the health system in sub-Saharan Africa. Parasite Epidemiol Control 2018;4:e00077. doi: 10.1016/j.parepi.2018.e00077 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Bustinduy A. An update on female and male genital schistosomiasis and a call to integrate efforts to escalate diagnosis, treatment and awareness in endemic and non-endemic settings: The time is now. Adv Parasitol 2022;115:1–44. doi: 10.1016/bs.apar.2021.12.003 [DOI] [PubMed] [Google Scholar]
- 148.Sturt A, Webb E, Patterson C, Phiri C, Mweene T, Kjetland E, et al. Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis. Front Immunol 2021;12:620657. doi: 10.3389/fimmu.2021.620657 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149.Dupnik K, Lee M, Mishra P, Reust M, Colombe S, Haider S, et al. Altered Cervical Mucosal Gene Expression and Lower Interleukin 15 Levels in Women With Schistosoma haematobium Infection but Not in Women With Schistosoma mansoni Infection. J Infect Dis 2019;219:1777–85. doi: 10.1093/infdis/jiy742 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Menezes C, Tasca T. Trichomoniasis immunity and the involvement of the purinergic signaling. Biomed J 2016;39:234–43. doi: 10.1016/j.bj.2016.06.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Barrios De Tomasi J, Opata M, Mowa C. Immunity in the Cervix: Interphase between Immune and Cervical Epithelial Cells. J Immunol Res 2019;2019:7693183. doi: 10.1155/2019/7693183 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Kitazawa J, Kimura F, Nakamura A, Morimune A, Takahashi A, Takashima A, et al. Endometrial Immunity for Embryo Implantation and Pregnancy Establishment. Tohoku J Exp Med 2020;250:49–60. doi: 10.1620/tjem.250.49 [DOI] [PubMed] [Google Scholar]
- 153.Groer M, Jevitt C, Ji M. Immune Changes and Dysphoric Moods across the Postpartum. Am J Reprod Immunol N Y N 1989 2015;73:193–8. doi: 10.1111/aji.12322 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Low N, Chersich M, Schmidlin K, Egger M, Francis S, van de Wijgert J H. H. M., et al. Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual Participant Data Meta-analysis. PLoS Med Vaginal Practices among Women at High Risk of HIV Infection in Uganda and Tanzania: Recorded Behaviour from a Daily Pictorial Diary;8:e1000416. doi: 10.1371/journal.pmed.1000416 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Francis S, Baisley K, Lees S, Andrew B, Zalwango F, Seeley J, et al. Vaginal Practices among Women at High Risk of HIV Infection in Uganda and Tanzania: Recorded Behaviour from a Daily Pictorial Diary. PLoS ONE 2013;8:e59085. doi: 10.1371/journal.pone.0059085 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Jourdan P, Holmen S, Gundersen S, Roald B, Kjetland E. HIV Target Cells in Schistosoma haematobium-Infected Female Genital Mucosa. Am J Trop Med Hyg 2011;85:1060–4. doi: 10.4269/ajtmh.2011.11-0135 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 157.Leutscher P, Pedersen M, Raharisolo C, Jensen J, Hoffmann S, Lisse I, et al. Increased Prevalence of Leukocytes and Elevated Cytokine Levels in Semen from Schistosoma haematobium–Infected Individuals. J Infect Dis 2005;191:1639–47. doi: 10.1086/429334 [DOI] [PubMed] [Google Scholar]
- 158.Mostafa M, Sheweita S, O’Connor P. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev 1999;12:97–111. doi: 10.1128/CMR.12.1.97 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 159.Mehrpouya-Bahrami P, Moriarty A, De Melo P, Keeter W, Alakhras N, Nelson A, et al. STAT4 is expressed in neutrophils and promotes antimicrobial immunity. JCI Insight 2021;6:e141326. doi: 10.1172/jci.insight.141326 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 160.Tindemans I, Serafini N, Di Santo J, Hendriks R. GATA-3 Function in Innate and Adaptive Immunity. Immunity 2014;41:191–206. doi: 10.1016/j.immuni.2014.06.006 [DOI] [PubMed] [Google Scholar]
- 161.El-Aal A, Emran A, Al-Antably A, El Saftawy E, Bayoumy I, Hassan N, et al. Immunohistochemical pattern of T lymphocytes population within bilharzial-associated bladder neoplasm microenvironment. Int J Immunopathol Pharmacol 2015;28:209–17. doi: 10.1177/0394632015584733 [DOI] [PubMed] [Google Scholar]
- 162.Mohammed S, Hetta H, Zahran A, Tolba M, Attia A, Behnsawy H, et al. T cell subsets, regulatory T, regulatory B cells and proinflammatory cytokine profile in Schistosoma haematobium associated bladder cancer: First report from Upper Egypt. PLoS Negl Trop Dis 2023;17:e0011258. doi: 10.1371/journal.pntd.0011258 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.El-Salahy E. Evaluation of cytokeratin-19 & cytokeratin-20 and interleukin-6 in Egyptian bladder cancer patients. Clin Biochem 2002;35:607–13. doi: 10.1016/S0009-9120(02)00382-X [DOI] [PubMed] [Google Scholar]
- 164.Knutson K, Disis M. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 2005;54:721–8. doi: 10.1007/s00262-004-0653-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Alehegne K, Mitiku B. Schistosoma mansoni Epidemiology Among Snails, Rodents and Children: A One Health Approach. Infect Drug Resist 2022;15:5629–43. doi: 10.2147/IDR.S363953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166.Fu C, Odegaard J, Herbert D, Hsieh M. A Novel Mouse Model of Schistosoma haematobium Egg-Induced Immunopathology. PLOS Pathog 2012;8:e1002605. doi: 10.1371/journal.ppat.1002605 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Hsieh J, Fu C, Hsieh M. Helminth-induced interleukin-4 abrogates invariant natural killer T cell activation-associated clearance of bacterial infection. Infect Immun 2014;82:2087–97. doi: 10.1128/IAI.01578-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168.Loc L, Mbanefo E, Khludenev G, Lamanna O, Banskota N, Hsieh M. Schistosoma haematobium cercarial infection alters subsequent systemic immune responses to eggs but has minimal impact on immune responses to egg injection of the bladder. Parasite Immunol 2019;41:e12602. doi: 10.1111/pim.12602 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169.Lane A, Boulanger D, Riveau G, Capron A, Wilson R. Murine immune responses to Schistosoma haematobium and the vaccine candidate rSh28GST. Parasite Immunol 1998;20:359–67. [PubMed] [Google Scholar]
- 170.Fu C, Odegaard J, Hsieh M. Macrophages are required for host survival in experimental urogenital schistosomiasis. The FASEB J 2015;29:193–207. doi: 10.1096/fj.14-259572 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Lord G, Matarese G, Howard J, Baker R, Bloom S, Lechler R. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;394:897–901. doi: 10.1038/29795 [DOI] [PubMed] [Google Scholar]
- 172.Richardson M, Fu C, Pennington L, Honeycutt J, Odegaard J, Hsieh Y, et al. A New Mouse Model for Female Genital Schistosomiasis. PLoS Negl Trop Dis 2014;8:e2825. doi: 10.1371/journal.pntd.0002825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Martinez F, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6:13. doi: 10.12703/P6-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174.Nair S, Bommana A, Bethony J, Lyon A, Ohshiro K, Pakala S, et al. The Metastasis-associated gene 1 encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer. Hepatol Baltim Md 2011;54:285–95. doi: 10.1002/hep.24354 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Ghanta K, Pakala S, Reddy S, Li D, Nair S, Kumar R. MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response. J Biol Chem 2011;286:7132–8. doi: 10.1074/jbc.M110.199273 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.He Y, Chen L, Ramaswamy K. Schistosoma mansoni, S. haematobium, and S. japonicum: early events associated with penetration and migration of schistosomula through human skin. Exp Parasitol 2002;102:99–108. doi: 10.1016/s0014-4894(03)00024-9 [DOI] [PubMed] [Google Scholar]
- 177.Marei H, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, et al. p53 signaling in cancer progression and therapy. Cancer Cell Int 2021;21:703. doi: 10.1186/s12935-021-02396-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 178.Schlüter C, Duchrow M, Wohlenberg C, Becker M, Key G, Flad H, et al. The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol 1993;123:513–22. doi: 10.1083/jcb.123.3.513 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Abdulamir A, Hafidh R, Kadhim H, Abubakar F. Tumor markers of bladder cancer: the schistosomal bladder tumors versus non-schistosomal bladder tumors. J Exp Clin Cancer Res 2009;28:27. doi: 10.1186/1756-9966-28-27 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 180.Bernardo C, Santos J, Costa C, Tavares A, Amaro T, Marques I, et al. Estrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferation. Urol Oncol Semin Orig Investig 2020;38:738.e23–738.e35. doi: 10.1016/j.urolonc.2020.04.022 [DOI] [PubMed] [Google Scholar]
- 181.Fujimoto K, Yamada Y, Okajima E, Kakizoe T, Sasaki H, Sugimura T, et al. Frequent Association of p53 Gene Mutation in Invasive Bladder Cancer1. Cancer Res 1992;52:1393–8. [PubMed] [Google Scholar]
- 182.Sidransky D, Von Eschenbach A, Tsai Y, Jones P, Summerhayes I, Marshall F, et al. Identification of p53 gene mutations in bladder cancers and urine samples. Science 1991;252:706–10. doi: 10.1126/science.2024123 [DOI] [PubMed] [Google Scholar]
- 183.Pycha A, Mian C, Posch B, Haitel A, El-Baz M, Ghoneim M, et al. Numerical aberrations of chromosomes 7, 9 and 17 in squamous cell and transitional cell cancer of the bladder: a comparative study performed by fluorescence in situ hybridization. J Urol 1998;160:737–40. doi: 10.1016/S0022-5347(01)62772-1 [DOI] [PubMed] [Google Scholar]
- 184.Shams T, Metawea M, Salim E. c-KIT Positive Schistosomal Urinary Bladder Carcinomas are Frequent but Lack KIT Gene Mutations. Asian Pac J Cancer Prev 2013;14:15–20. doi: 10.7314/APJCP.2013.14.1.15 [DOI] [PubMed] [Google Scholar]
- 185.Mursi K, Agag A, Hammam O, Riad M, Daw M. The expression of p63 in bladder cancer vs. chronic bilharzial bladder. Arab J Urol 2013;11:106–12. doi: 10.1016/j.aju.2012.12.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 186.Nagata S. Apoptosis by Death Factor. Cell 1997;88:355–65. doi: 10.1016/s0092-8674(00)81874-7 [DOI] [PubMed] [Google Scholar]
- 187.Elmansy H, Kotb A, Hammam O, AbdelRaouf H, Salem H, Onsi M, et al. Prognostic impact of apoptosis marker Fas (CD95) and its ligand (FasL) on bladder cancer in Egypt: study of the effect of schistosomiasis. Ecancermedicalscience 2012;6:278. doi: 10.3332/ecancer.2012.278 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Han J, Li G, Wan P-P, Zhu T, Meng Q. Identification of glutathione S-transferase genes in Leptinotarsa decemlineata and their expression patterns under stress of three insecticides. Pestic Biochem Physiol 2016;133:26–34. doi: 10.1016/j.pestbp.2016.03.008 [DOI] [PubMed] [Google Scholar]
- 189.Sheweita S, Abu El-Maati M, El-Shahat F, Bazeed M. Changes in the expression of cytochrome P450 2E1 and the activity of carcinogen-metabolizing enzymes in Schistosoma haematobium-infected human bladder tissues. Toxicology 2001;162:43–52. doi: 10.1016/s0300-483x(01)00357-2 [DOI] [PubMed] [Google Scholar]
- 190.Chen C. COX-2’s new role in inflammation. Nat Chem Biol 2010;6:401–2. doi: 10.1038/nchembio.375 [DOI] [PubMed] [Google Scholar]
- 191.Swana H, Smith S, Perrotta P, Saito N, Wheeler M, Weiss R. Inducible nitric oxide synthase with transitional cell carcinoma of the bladder. J Urol 1999;161:630–4. doi: 10.1016/S0022-5347(01)61985-2 [DOI] [PubMed] [Google Scholar]
- 192.Khayoon S, Al-Omashi G. Cyclooxygenase-2 Level in Bilharzial and Non-Bilharzial Related Bladder Cancer among Iraqi Patients. Indian J Forensic Med Toxicol 2021;15:3488–92. doi: 10.37506/ijfmt.v15i2.14915 [DOI] [Google Scholar]
- 193.Hassan H, Mohamed A, Bakhiet A, Ahmed H. Immunohistochemical expression of COX2 and iNOS in bladder cancer and its association with urinary schistosomiasis among Sudanese patients. Infect Agent Cancer 2013;8:9. doi: 10.1186/1750-9378-8-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 194.Salim E, Morimura K, Menesi A, El-Lity M, Fukushima S, Wanibuchi H. Elevated oxidative stress and DNA damage and repair levels in urinary bladder carcinomas associated with schistosomiasis. Int J Cancer 2008;123:601–8. doi: 10.1002/ijc.23547 [DOI] [PubMed] [Google Scholar]
- 195.Guo C, Li Z, Wang R, Yu J, Ye M, Mao L, et al. Association between Oxidative DNA Damage and Risk of Colorectal Cancer: Sensitive Determination of Urinary 8-Hydroxy-2′-deoxyguanosine by UPLC-MS/MS Analysis. Sci Rep 2016;6:32581. doi: 10.1038/srep32581 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Bernardo C, Cunha M, Santos J, da Costa J, Brindley P, Lopes C, et al. Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics. Tumor Biol 2016;37:11279–87. doi: 10.1007/s13277-016-4997-y [DOI] [PubMed] [Google Scholar]
- 197.Rushing B, Selim M. Aflatoxin B1: A review on metabolism, toxicity, occurrence in food, occupational exposure, and detoxification methods. Food Chem Toxicol 19AD;124:81–100. doi: 10.1016/j.fct.2018.11.047 [DOI] [PubMed] [Google Scholar]
- 198.Habib S, Said B, Awad A, Mostafa M, Shank R. Novel adenine adducts, N7-guanine-AFB1 adducts, and p53 mutations in patients with schistosomiasis and aflatoxin exposure. Cancer Detect Prev 2006;30:491–8. doi: 10.1016/j.cdp.2006.10.006 [DOI] [PubMed] [Google Scholar]
- 199.Zhong X, Isharwal S, Naples J, Shiff C, Veltri R, Shao C, et al. Hypermethylation of Genes Detected in Urine from Ghanaian Adults with Bladder Pathology Associated with Schistosoma haematobium Infection. PLOS ONE 2013;8:e59089. doi: 10.1371/journal.pone.0059089 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 200.Hartgers F, Obeng B, Kruize Y, Duijvestein M, de Breij A, Amoah A, et al. Lower Expression of TLR2 and SOCS-3 Is Associated with Schistosoma haematobium Infection and with Lower Risk for Allergic Reactivity in Children Living in a Rural Area in Ghana. PLoS Negl Trop Dis 2008;2:e227. doi: 10.1371/journal.pntd.0000227 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 201.Wetzler L. The role of Toll-like receptor 2 in microbial disease and immunity. Vaccine 2003;21:S55–60. doi: 10.1016/s0264-410x(03)00201-9 [DOI] [PubMed] [Google Scholar]
- 202.Layland L, Straubinger K, Ritter M, Loffredo-Verde E, Garn H, Sparwasser T, et al. Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells. PLoS Negl Trop Dis 2013;7:e2379. doi: 10.1371/journal.pntd.0002379 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 203.Sitcharungsi R, Sirivichayakul C. Allergic diseases and helminth infections. Pathog Glob Health 2013;107:110–5. doi: 10.1179/2047773213Y.0000000080 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204.Pelgrom LR, Everts B. Metabolic control of type 2 immunity. Eur J Immunol 2017;47:1266–75. doi: 10.1002/eji.201646728 [DOI] [PubMed] [Google Scholar]
- 205.Dupnik K, Reust M, Vick K, Yao B, Miyaye D, Lyimo E, et al. Gene Expression Differences in Host Response to Schistosoma haematobium Infection. Infect Immun 2018;87:e00291–18. doi: 10.1128/IAI.00291-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Shariati F, Pérez-Arellano J, Carranza C, López-Abán J, Vicente B, Arefi M, et al. Evaluation of the role of angiogenic factors in the pathogenesis of schistosomiasis. Exp Parasitol 2001;128:44–9. doi: 10.1016/j.exppara.2011.01.016 [DOI] [PubMed] [Google Scholar]
- 207.Sheweita S, Mostafa M, Ebid F, El-Sayed W. Changes in expression and activity of glutathione S-transferase in different organs of schistosoma haematobium-infected hamster. J Biochem Mol Toxicol 2003;17:138–45. doi: 10.1002/jbt.10071 [DOI] [PubMed] [Google Scholar]
- 208.Chala B, Choi M, Moon K, Kim H, Kwak C, Hong S. Development of Urinary Bladder Pre-Neoplasia by Schistosoma haematobium Eggs and Chemical Carcinogen in Mice. Korean J Parasitol 2017;55:21–9. doi: 10.3347/kjp.2017.55.1.21 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Botelho M, Veiga I, Oliveira P, Lopes C, Teixeira M, da Costa J, et al. Carcinogenic ability of Schistosoma haematobium possibly through oncogenic mutation of KRAS gene. Adv Cancer Res Treat 2013;2013:876585. [PMC free article] [PubMed] [Google Scholar]
- 210.Ouerhani S, Bougatef K, Soltani I, Elgaaied A, Abbes S, Menif S. The prevalence and prognostic significance of KRAS mutation in bladder cancer, chronic myeloid leukemia and colorectal cancer. Mol Biol Rep 2013;40:4109–14. doi: 10.1007/s11033-013-2512-8 [DOI] [PubMed] [Google Scholar]
- 211.Osakunor D, Ishida K, Lamanna O, Rossi M, Dwomoh L, Hsieh M. Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology. PLoS Negl Trop Dis 2022;16:e0010176. doi: 10.1371/journal.pntd.0010176 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 212.Ray D, Nelson T, Fu C, Patel S, Gong D, Odegaard J, et al. Transcriptional Profiling of the Bladder in Urogenital Schistosomiasis Reveals Pathways of Inflammatory Fibrosis and Urothelial Compromise. PLoS Negl Trop Dis 2012;6:e1912. doi: 10.1371/journal.pntd.0001912 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 213.Mbanefo E, Fu C, Ho C, Le L, Ishida K, Hammam O, et al. Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis. Infect Immun 2020;88: doi: 10.1128/iai.00669-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 214.Botelho M, Ferreira A, Oliveira M, Domingues A, Machado J, da Costa J. Schistosoma haematobium total antigen induces increased proliferation, migration and invasion, and decreases apoptosis of normal epithelial cells. Int J Parasitol 2009;39:1083–91. doi: 10.1016/j.ijpara.2009.02.016 [DOI] [PubMed] [Google Scholar]
- 215.Adebayo A, Survayanshi M, Bhute S, Agunloye A, Isokpehi R, Anumudu C, et al. The microbiome in urogenital schistosomiasis and induced bladder pathologies. PLoS Negl Trop Dis 2017;11:e0005826. doi: 10.1371/journal.pntd.0005826 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 216.Kay G, Millard A, Sergeant M, Midzi N, Gwisai R, Mduluza T, et al. Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. PLoS Negl Trop Dis 2015;9:e0003861. doi: 10.1371/journal.pntd.0003861 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Osakunor D, Munk P, Mduluza T, Petersen T, Brinch C, Ivens A, et al. The gut microbiome but not the resistome is associated with urogenital schistosomiasis in preschool-aged children. Commun Biol 2020;3:155. doi: 10.1038/s42003-020-0859-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 218.Azar J, Schraibman I, Pitchford R. Some observations on Schistosoma habmatobium in the human rectum and sigmoid. Trans R Soc Trop Med Hyg 1958;52:562–4. doi: 10.1016/0035-9203(58)90105-6 [DOI] [PubMed] [Google Scholar]
- 219.Cnops L, Soentjens P, Clerinx J, Esbroeck M. A Schistosoma haematobium-Specific Real-Time PCR for Diagnosis of Urogenital Schistosomiasis in Serum Samples of International Travelers and Migrants. PLoS Negl Trop Dis 2013;7:e2413. doi: 10.1371/journal.pntd.0002413 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Schneeberger P, Coulibaly J, Panic G, Daubenberger C, Gueuning M, Frey J, et al. Investigations on the interplays between Schistosoma mansoni, praziquantel and the gut microbiome. Parasit Vectors 2018;11:168. doi: 10.1186/s13071-018-2739-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221.] Rambau P, Chalya P, Jackson K. Schistosomiasis and urinary bladder cancer in North Western Tanzania: a retrospective review of 185 patients. Infect Agent Cancer 2013;8:19. doi: 10.1186/1750-9378-8-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 222.Stojanov S, Berlec A, Štrukelj B. The Influence of Probiotics on the Firmicutes/Bacteroidetes Ratio in the Treatment of Obesity and Inflammatory Bowel disease. Microorganisms 2020;8:1715. doi: 10.3390/microorganisms8111715 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 223.Amabebe E, Robert F, Agbalalah T, Orubu E. Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism. Br J Nutr 2020;123:1127–37. doi: 10.1017/S0007114520000380 [DOI] [PubMed] [Google Scholar]
- 224.Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol 2015;37:47–55. doi: 10.1007/s00281-014-0454-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 225.Yang M, Gu Y, Li L, Liu T, Song X, Sun Y, et al. Bile Acid—Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside. Nutrients 2021;13:3143. doi: 10.3390/nu13093143 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 226.Gosmann C, Anahtar M, Handley S, Farcasanu M, Abu-Ali G, Bowman B, et al. Lactobacillus-Deficient Cervicovaginal Bacterial Communities are Associated with Increased HIV Acquisition in Young South African Women. Immunity 2017;46:29–37. doi: 10.1016/j.immuni.2016.12.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 227.Masson L, Passmore J, Liebenberg L, Werner L, Baxter C, Arnold K, et al. Genital Inflammation and the Risk of HIV Acquisition in Women. Clin Infect Dis 2015;61:260–9. doi: 10.1093/cid/civ298 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 228.Bullington B, Lee M, Mlingi J, Paul N, Aristide C, Fontana E, et al. Cervicovaginal bacterial communities in reproductive-aged Tanzanian women with Schistosoma mansoni, Schistosoma haematobium, or without schistosome infection. ISME J 2021;15:1539–50. doi: 10.1038/s41396-020-00868-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 229.Sturt A, Webb E, Himschoot L, Phiri C, Mapani J, Mudenda M, et al. Association of Female Genital Schistosomiasis With the Cervicovaginal Microbiota and Sexually Transmitted Infections in Zambian Women. Open Forum Infect Dis 2021;8:ofab438. doi: 10.1093/ofid/ofab438 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 230.Masha S, Cools P, Sanders E, Vaneechoutte M, Crucitti T. Trichomonas vaginalis and HIV infection acquisition: a systematic review and meta-analysis. Sex Transm Infect 2019;95:36–42. doi: 10.1136/sextrans-2018-053713 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 231.Mavedzenge S, Van Der Pol B, Cheng H, Montgomery E, Blanchard K, de Bruyn G, et al. Epidemiological Synergy of Trichomonas vaginalis and HIV in Zimbabwean and South African Women. Sex Transm Dis 2010;37:460–6. doi: 10.1097/OLQ.0b013e3181cfcc4b [DOI] [PubMed] [Google Scholar]
- 232.Wang C, McClelland R, Reilly M, Overbaugh J, Emery S, Mandaliya K, et al. The Effect of Treatment of Vaginal Infections on Shedding of Human Immunodeficiency Virus Type 1. J Infect Dis 2001;183:1017–22. doi: 10.1086/319287 [DOI] [PubMed] [Google Scholar]
- 233.Kissinger P, Amedee A, Clark R, Dumestre J, Theall K, Myers L, et al. Trichomonas Vaginalis Treatment Reduces Vaginal HIV-1 Shedding. Sex Transm Dis 2009;36:11. doi: 10.1097/OLQ.0b013e318186decf [DOI] [PMC free article] [PubMed] [Google Scholar]
- 234.Anderson B, Firnhaber C, Liu T, Swarts A, Siminya M, Ingersoll J, et al. Effect of Trichomoniasis Therapy on Genital HIV Viral Burden Among African Women. Sex Transm Dis 2012;39:638. doi: 10.1097/OLQ.0b013e31825725ad [DOI] [PMC free article] [PubMed] [Google Scholar]
- 235.IARC Working Group. Schistosoma haematobium. Biol. Agents, International Agency for Research on Cancer; 2012.
- 236.Cromarty R, Archary D. Inflammation, HIV, and Immune Quiescence: Leveraging on Immunomodulatory Products to Reduce HIV Susceptibility. AIDS Res Treat 2020;2020:8672850. doi: 10.1155/2020/8672850 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 237.Gumbi P, Nkwanyana N, Bere A, Burgers W, Gray C, Williamson A, et al. Impact of Mucosal Inflammation on Cervical Human Immunodeficiency Virus (HIV-1)-Specific CD8 T-Cell Responses in the Female Genital Tract during Chronic HIV Infection. J Virol 2008;82:8529–36. doi: 10.1128/JVI.00183-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238.Arnold K, Burgener A, Birse K, Romas L, Dunphy L, Shahabi K, et al. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol 2016;9:194–205. doi: 10.1038/mi.2015.51 [DOI] [PubMed] [Google Scholar]
- 239.Turner J. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799–809. doi: 10.1038/nri2653 [DOI] [PubMed] [Google Scholar]
- 240.Loffredo-Verde E, Bhattacharjee S, Malo A, Festag J, Kosinska A, Ringelhan M, et al. Dynamic, Helminth-Induced Immune Modulation Influences the Outcome of Acute and Chronic Hepatitis B Virus Infection. J Infect Dis 2020;221:1448–61. doi: 10.1093/infdis/jiz594 [DOI] [PubMed] [Google Scholar]
- 241.Porto A, Santos S, Muniz A, Basílio V, Rodrigues W Jr., Neva F, et al. Helminthic Infection Down-Regulates Type 1 Immune Responses in Human T Cell Lymphotropic Virus Type 1 (HTLV-1) Carriers and Is More Prevalent in HTLV-1 Carriers than in Patients with HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis. J Infect Dis 2005;191:612–8. doi: 10.1086/427560 [DOI] [PubMed] [Google Scholar]
- 242.Moreno-Fernandez M, Zapata W, Blackard J, Franchini G, Chougnet CA. Human Regulatory T Cells Are Targets for Human Immunodeficiency Virus (HIV) Infection, and Their Susceptibility Differs Depending on the HIV Type 1 Strain. J Virol 2009;83:12925–33. doi: 10.1128/JVI.01352-09 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 243.Greten F, Grivennikov S. Inflammation and Cancer: Triggers, Mechanisms and Consequences. Immunity 2019;51:27–41. doi: 10.1016/j.immuni.2019.06.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 244.Tosti E, Srivastava N, Edelmann W. Vaccination and Microbiota Manipulation Approaches for Colon Cancer Prevention in Rodent Models. Cancer Prev Res (Phila Pa) 2023;16:429–38. doi: 10.1158/1940-6207.CAPR-23-0015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 245.Donaldson G, Lee S, Mazmanian S. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 2016;14:20–32. doi: 10.1038/nrmicro3552 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 246.Ramanan D, Sefik E, Galván-Peña S, Wu M, Yang L, Yang Z, et al. An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint. Cell 2020;181:1276–1290.e13. doi: 10.1016/j.cell.2020.04.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 247.Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med 2018;24:392–400. doi: 10.1038/nm.4517 [DOI] [PMC free article] [PubMed] [Google Scholar]