Beyond schistosomiasis: unraveling co-infections and altered immunity

SUMMARY

Schistosomiasis is a neglected tropical disease caused by the helminth Schistosoma spp. and has the second highest global impact of all parasites. Schistosoma are transmitted through contact with contaminated fresh water predominantly in Africa, Asia, the Middle East, and South America. Due to the widespread prevalence of Schistosoma, co-infection with other infectious agents is common but often poorly described. Herein, we review recent literature describing the impact of Schistosoma co-infection between species and Schistosoma co-infection with blood-borne protozoa, soil-transmitted helminths, various intestinal protozoa, Mycobacterium, Salmonella, various urinary tract infection-causing agents, and viral pathogens. In each case, disease severity and, of particular interest, the immune landscape, are altered as a consequence of co-infection. Understanding the impact of schistosomiasis co-infections will be important when considering treatment strategies and vaccine development moving forward.

INTRODUCTION

Approximately 10% of the world’s population is at risk of infection with Schistosoma spp. parasites, which cause the debilitating disease called schistosomiasis, also known as bilharzia (1). Schistosomiasis is the second most important parasitic disease behind only malaria in terms of global impact (2). Spread through contact with contaminated fresh water, schistosomiasis leads to chronic morbidities that can last for over 40 years and life-threatening health conditions if left untreated (3). Schistosomiasis remains a major epidemiological concern, affecting wide geographical regions, comprising primarily low- to middle-income countries (1, 2). Due to this parasite’s widespread distribution, endemic regions often overlap with areas of endemicity for other pathogens (e.g., malaria, leishmaniasis, and more). Despite geographical overlaps of infection occurrence and numerous works demonstrating the ways Schistosoma helminths modulate the immune system (4–6), there remains a gap of knowledge in the effects of this parasite on co-infecting pathogens and how co-exposure may affect prognosis (7).

Schistosomiasis is caused by three main species in humans: Schistosoma mansoni, S. haematobium, and S. japonicum. Schistosomiasis pathology varies based on the infecting species; S. haematobium results in urinary schistosomiasis, while S. mansoni and S. japonicum result in intestinal schistosomiasis (3).

Schistosomiasis is commonly found in tropical and subtropical regions of Africa, Asia, the Middle East, and South America. While schistosomiasis transmission occurs in over 70 countries (8), 90% of cases occur in sub-Saharan Africa (9, 10). Within Asia, the disease is common in China, the Philippines, and Indonesia, while in South America, Brazil and Venezuela have the highest rates of infection (8). Regions where this parasite is spread often lack infrastructure and clean water sources, leaving the population vulnerable to infection through contaminated freshwater sources such as rivers, lakes, and ponds (3, 8). Despite efforts to control the spread of schistosomiasis, it remains a significant public health problem worldwide.

SCHISTOSOMA CONTROL CHALLENGES

Individuals with schistosomiasis can be effectively treated with praziquantel (PZQ) which for years has been used to prevent long-term complications of chronic infection (8). PZQ is a helminth paralytic which disrupts the nervous system of adult worms leading to parasite death (11). Despite its safety and efficacy, PZQ alone has not been sufficient to eliminate schistosomiasis. Furthermore, it has been difficult to treat all individuals affected by schistosomiasis through mass drug administration (MDA). There are more cases of infection than doses of drug available, and many of those affected are unable to access treatment, particularly those living in rural areas (12, 13). In addition to the limitations of PZQ, schistosomiasis has been difficult to eliminate for many other reasons. For example, S. japonicum can infect other mammals, allowing the population of animals perpetuating the life cycle to expand beyond humans alone. Furthermore, diagnosis is imperfect, and cases of low-level infections exist, allowing those without overtly debilitating symptoms to go undiagnosed and untreated (14). The development of vaccines for this parasite has been underway since the 1970s (15–19), although none have yet been approved for human use, and more importantly, high efficacy has been elusive (20).

The presence of Schistosoma spp. in a particular area depends on the presence of the specific species’ intermediate snail vector(s) (21). As snail habitats have changed over time due to factors such as modifications of waterways [dams and irrigation schemes (22, 23)] and climate change (24), Schistosoma endemicity has and continues to change. One well documented occurrence of such changing endemicity occurred in the Senegal River Basin in the early 1990s. Prior to the building of two dams in the region, intestinal schistosomiasis was not found in the Senegal River Basin, and urogenital schistosomiasis rates were low (25, 26). Two years after the opening of the first dam, an outbreak of intestinal (S. mansoni) schistosomiasis occurred in Richard-Toll, a town on the Senegal River in the lower Senegal River Basin (27, 28). Within 6 years of the dam opening, both S. mansoni and S. haematobium were widespread throughout the Lac de Guiers region, which is connected to the Senegal River at Richard-Toll by an intake canal (25). Differently, the effects of climate change can be seen clearly in the outbreak (24, 29) and potential continuing endemicity (30, 31) of urogenital schistosomiasis in Corsica, France. The outbreak first occurred in 2013, but cases have been linked to the region as recently as 2019 (30, 31). The parasites responsible for these cases are S. haematobium × S. bovis hybrids genetically closest to the Schistosoma of the Senegal River Basin (32); their establishment in Corsica is thought to be due to warming temperatures, the existence of a suitable snail vector already present in the region, and increasing migration/movement between endemic regions of Senegal/West Africa and France (29, 33). These two examples, of the Senegal River Basin and Corsica, highlight the importance of effective schistosomiasis monitoring. Moreover, when considering the constraints of PZQ and untreated infections, these examples illustrate the challenges of eliminating schistosomiasis and shed light on its widespread global presence.

CO-ENDEMICITY

Due to the prevalence of schistosomiasis (over 250 million infections yearly) and its broad geographical distribution (8), co-infections of Schistosoma spp. and other pathogens are common (7). As this parasite is common in low- to middle-income countries, affected individuals may be unaware of their co-infections and/or have limited access to treatment for them. Some common co-infections which affect Schistosoma spp. positive individuals include soil-transmitted helminths (STHs) (34), malaria (35), human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (36), and tuberculosis (TB) (37).

Helminth infections are known to be formidable modulators of the host immune response, so it is understandable why many reviews have sought to determine the effects of these helminths during cases of co-infection (38–40). Although classified as a helminth, Schistosoma spp. carry unique traits which separate them from the rest. For instance, schistosomes are non-hermaphroditic trematodes which reside in the vascular system, rather than the gut lumen (3). Therefore, it is worth exploring the effect schistosomes, specifically, have on co-infecting pathogens and vice versa. Here, we explore co-infections with major parasitic, bacterial, and viral pathogens which have been reported to be co-endemic with schistosomiasis. The pathogens discussed have been chosen based on frequency, geographical sizes of co-endemic regions, global impact, and the availability of research. Additionally, we discuss the epidemiology and immune mechanisms of co-infections within animal models and, where available, in human data.

SCHISTOSOMA PATHOGENESIS

The prevalence of schistosomiasis is complicated by its elaborate life cycle involving a snail vector. Eggs released into fresh water hatch miracidia, the first larval stage of Schistosoma parasites. Free-swimming miracidia infect different snail vectors in a species-dependent manner: S. mansoni infects Biomphalaria spp., S. haematobium infects Bulinus spp., and S. japonicum infects Oncomelania spp. snails. Within the snail, miracidia become sporocysts and undergo several rounds of asexual reproduction, giving rise to cercariae. Cercariae, the next larval stage of Schistosoma spp., exit the snail and swim through the water. Upon contact with a mammal, the definitive host, they actively penetrate the skin. Once inside the epidermis, cercariae shed their tails, transforming into schistosomula, and reside within the dermis for around 3 days. Penetrating larvae drive the expression of programmed death ligands, PD-L1 and -L2, as well as IL-10 by human dermal dendritic cells (DCs; demonstrated in ex vivo human skin explants), promoting a regulatory phenotype (41). Cercarial penetration may also lead to the development of cercarial dermatitis or “swimmer’s itch.” As the infection continues, schistosomiasis generally presents with mild symptoms and shifts toward T-helper-1 (T_H1) skewing immune responses (4) with increases of pro-inflammatory cytokines IL-1, IL-6, and TNFα in peripheral blood (42). During this time, schistosomula make their way into the circulation and travel to the lungs. Within the lungs, the parasite thins and elongates over the course of approximately 7 days, before following the circulation to the liver where the final larval stage matures into juvenile worms. The lung stage of the parasite tends to result in cold and flu-like symptoms including the allergic response, Katayama fever (43), and eosinophilic infiltrates which create lesions visible by radiography (44). In the hepatic portal vein, male and female worms mature and pair, then travel together to the mesentery of the intestines for most Schistosoma spp., except for S. haematobium, where adult worms take residence in the veins around the bladder. Severe pathology takes place as adult worms begin laying eggs. Depending on the species, Schistosoma female worms can lay upward of 300 eggs/per day, half of which are released with excreta, whereas the other portion is embedded within host tissues. Schistosoma eggs are highly immunogenic, and the secretion of soluble egg antigens (SEA) shifts immune responses toward T-helper-2 (T_H2) mediators (45). These SEA cause a strong influx of immune cells, triggering inflammation and granuloma development, which is important for host protection and parasite egg egress (46, 47). Chronic schistosomiasis leads to an increase in regulatory T (T_REG) cell responses, cirrhosis, and organ fibrosis and failure, if left untreated. S. haematobium infection can also result in genital schistosomiasis (48–50) and cervical neoplasia (51), in addition to being a major causative agent of bladder cancer (52).

Although the pathobiology of Schistosoma spp. is generally well described and is summarized in Fig. 1, how this parasite behaves in cases of co-infection has yet to be thoroughly explored.

Fig 1.

Schistosoma pathobiology. Intestinal schistosomiasis is represented by Schistosoma mansoni (Sm) transmitted by Biomphalaria spp. snails, and urinary schistosomiasis is represented by S. haematobium (Sh) transmitted by Bulinus spp. snails. Upon cercarial entry into the skin, schistosomes induce T_REG responses. From circulation to adult worm oviposition, immune responses are predominately T_H1. As adult worms pair and lay eggs in the intestinal mesentery (Sm) and bladder venus plexus (Sh), soluble egg antigens drive T_H2 immunity. Eggs are excreted in feces (Sm) and urine (Sh) to continue the life cycle. Chronic schistosomiasis upregulates T_REG responses to protect the host from severe pathology and promote parasite persistence. Illustrative images are not to scale.

SCHISTOSOMA CO-INFECTION BETWEEN SPECIES

Two of the three most common human-infecting Schistosoma species, S. mansoni and S. haematobium, have significantly overlapping endemic areas including much of sub-Saharan Africa and parts of Egypt and the Middle East (21). Given that most Schistosoma infections occur in co-endemic sub-Saharan Africa (8), interspecies co-infection is a significant risk (53). While research is lacking on the epidemiology and morbidity of co-infections at a large scale (country/global), there is a growing body of work at the local scale (village/region), notably in Senegal (53–58), Cameroon (23, 59), Nigeria (60), Ghana (61), Kenya (62), Niger (55), and Mali (55, 63). In many of the areas investigated, more than half of infected individuals were co-infected with multiple Schistosoma species (53, 56, 61). Mixed infections were consistently associated with changes in egg elimination patterns, infection intensity, and morbidity.

One common indicator of co-infection with S. mansoni and S. haematobium is ectopic egg elimination, which refers to S. haematobium eggs eliminated in the stool and/or S. mansoni eggs eliminated in the urine (Fig. 2). This phenomenon can sometimes be attributed to unusual worm localization or “spillover” from typical egg laying sites in mono-infections, particularly in the case of high parasite burdens (23). More commonly, however, ectopic egg elimination is associated with co-infections and occurs due to heterospecific mating between different Schistosoma species (23, 58, 61). When worms of both species are present in an individual, heterospecific mating (when a male of one species couples with a female of another) can occur in the hepatic portal vein (64). The species of the male schistosome will determine where the couple migrates and lays eggs. S. haematobium schistosomes have a higher male to female ratio (23) than S. mansoni schistosomes and an increased ability to “steal” females from already established pairings (65). These differences explain the higher frequency of S. mansoni eggs found in urine compared to S. haematobium eggs found in stool (23, 53, 58, 59, 61). While ectopic egg elimination has been documented as early as the late 19th century (66), it remains poorly examined and as such it is difficult to accurately estimate its prevalence. The effect of ectopic eggs on the host is also not fully understood in the context of co-infection. However, given that eggs drive schistosomiasis pathology, their presence in “non-traditional” locations could have consequences for infection morbidity, as observed in ectopic mono-infections (67).

Fig 2.

Schistosoma mansoni (Sm) and S. haematobium (Sh) co-infection. In co-infections with Sm and Sh, ectopic egg elimination occurs, with both Sm and Sh eggs found in urine and, to a lesser extent, in feces. Male worms determine the residency of paired couples. Sm male and Sh female couplings (M) are more common, these pairs reside in the venous plexus similar to Sh couples; Sm couples reside within the intestinal mesentery. Co-infection reduces the risk of liver pathology but increases parasite burdens, urogenital pathology, and T_H2 immune responses. Illustrative images are not to scale.

Multiple studies have found that higher infection intensities occur in co-infection vs mono-infection with Schistosoma species. An association between high infection burdens and mixed infections has been observed in studies in Niger (68); Niger, Mali, and Senegal (55); the Senegal River Basin (53); Ghana (61); and Cameroon (23). Taken together, these studies suggest a notable effect of co-infection on infection intensity, which is an important consideration for surveillance, treatment, and control efforts. Thus far, multiple studies have shown that PZQ treatment efficacy is equally effective in mono-infections and co-infections (68, 69). However, because co-infections were generally higher burden infections, the dose of PZQ may not be as effective for clearance as in lower burden mono-infections (55). Additional research is needed to fully understand the association between co-infection and higher infection burden, and whether this relationship affects PZQ treatment efficacy.

There have been notable differences in morbidity observed in co-infections with S. mansoni and S. haematobium compared to single-species infections. Specifically, hepatic and splenic pathologies appear to decrease in co-infections, while bladder pathologies tend to increase. In Cameroon, it was found that hepatomegaly and splenomegaly (assessed by physical exam) were less common in co-infections than in S. mansoni mono-infections (23). Similarly, in Mali, ultrasonographic examination showed a decreased risk for abnormal liver imaging for co-infected vs S. mansoni mono-infected [standardized for level of infection (63)]. It was also found that the risk of hepatomegaly was higher in individuals mono-infected with either S. mansoni or S. haematobium than in co-infected individuals; in contrast, bladder pathology was increased in co-infections over S. haematobium mono-infections (63). It is hypothesized that this effect can be attributed to S. haematobium males outcompeting S. mansoni males for mates, resulting in a greater number of S. mansoni females directed to the bladder venous plexus instead of the mesentery of the intestines (65). This shift in worm pair location would lead to preferential egg entrapment and pathology in the bladder versus the liver. Interestingly, one study in Kenya found that bladder pathology was decreased in co-infections compared to S. haematobium mono-infections (62), which may be a result of different sampling techniques or point to population differences, both in terms of humans and parasites. As schistosomiasis epidemiology is highly focal, morbidity varies between locations. This is exemplified by a study in the Senegal River Basin, which found a strong geospatial cluster for severe hepatic fibrosis within the co-endemic region (57). Overall, it appears that the hallmark pathology of S. mansoni is decreased in co-infection, while the pathology of S. haematobium is increased. Still, broader investigations are needed to fully understand the effect of co-infection on morbidity throughout large co-endemic regions.

To date, minimal research has been conducted on the immunology of S. mansoni and S. haematobium co-infections. In general, schistosome immunology research is heavily biased toward S. mansoni, in part due to the lack of a rodent model that accurately recapitulates the life cycle of S. haematobium in humans (70). While Schistosoma immune responses share many similarities, there may be underappreciated species-specific effects, including immunopathology and cancers of the bladder and genital regions, and a lower incidence of hypersensitivity reactions (e.g., cercarial dermatitis and Katayama syndrome) observed in S. haematobium infections (70). When whole blood from individuals living in a co-endemic region was cultured with either S. haematobium or S. mansoni antigens, cytokine responses were similar, and there was an inverse correlation between cytokine responses and Schistosoma infection intensities. Strong T_H1 responses were observed in uninfected samples, an intermediate profile was found in single infections and light infections, and a T_H2 bias (and lower general response) was found in mixed and heavy infections. Unfortunately, due to the confounding effect of infection intensity, it is unclear whether this gradient in cytokine response is due to the co-infection or the higher parasite burdens seen in that population (56).

Further complicating the picture, co-infections with multiple schistosome species can also lead to species hybridization. Schistosoma hybridization has important implications for host range (vertebrate and snail), pathology, and epidemiology (71, 72). During co-infection, when heterospecific pairing occurs, there is a possibility for parthenogenesis (asexual reproduction resulting in eggs containing only the female’s genome), hybridization (full mixture between the parental genomes), and introgression (transfer of genes/chromosomal regions between species through backcrossing) (64, 73). The likelihood of hybridization between two species is related to their phylogenetic distance, with intraclade hybridizations more frequently observed and established in the literature (71). For instance, hybrids identified in West Africa as well as Corsica, France consist of S. haematobium and the bovine species S. bovis (71). It was previously believed that phylogenetically divergent species, such as S. haematobium and S. mansoni, could not hybridize and that eggs from these heterospecific pairings would be purely parthenogenic. However, over the past decade, there has been growing evidence of hybridization between these two species in humans (74–76). Ectopic egg elimination is one effect of interspecific pairings, but given the lack of genotyping evidence, it is not known to what extent those eggs are parthenogenic or hybridized. Hybridization can also affect the host range of the parasite, leading to changes in zoonotic transmission dynamics as seen with S. haematobium × S. bovis hybrids (71). It is also important to consider the effects of hybridization on morbidity profiles, PZQ efficacy, and vaccine development. With continuing changes in human migration, climate, and irrigation and development, interactions between different species of schistosomes and their hosts are likely to continue to shift and increase (71, 72). To keep pace with this rapidly changing landscape, it is imperative to implement more effective surveillance efforts for both co-infections and hybridization events and to investigate these phenomena in the laboratory.

Co-infections with multiple schistosome species and infections with hybridized species are currently underrecognized and understudied. On a local level, multiple studies in S. mansoni and S. haematobium co-endemic areas have found that co-infection is the norm (53, 56, 61) leading to trends of increased worm burdens (23, 53, 55, 61, 68) and ectopic egg elimination (23, 53, 58, 59, 61). Morbidity associated with S. haematobium appears to increase in co-infection, while S. mansoni-associated morbidity decreases (23, 63); future work should assess if these co-infections result in increased manifestations of genital schistosomiasis. These observations need to be validated in larger studies in more locations, and a greater understanding of the effects of co-infection and hybrid infection on immunology, morbidity, diagnosis, treatment, and transmission is necessary.

SOIL-TRANSMITTED HELMINTHS

Soil-transmitted helminths are a group of intestinal parasites infecting up to a quarter of the world’s population. STHs cause neglected tropical diseases which primarily affect impoverished communities with limited access to sanitation in tropical and subtropical regions, especially in sub-Saharan Africa, South America, and Asia. There are three main types of STH: Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and hookworms (e.g., Necator americanus and Ancylostoma duodenale). Additionally, Strongyloides stercoralis (threadworm) is an STH but is often excluded from analyses and control efforts due to differences in diagnosis and treatment compared to the other three STHs (77). Light infections with STHs are typically asymptomatic, but heavier infections can cause a variety of symptoms including diarrhea and abdominal pain, anemia, nutrient deficiency, malnutrition, growth impairment, and intestinal blockage (77, 78). Effective deworming treatments exist for STHs, typically albendazole and mebendazole for the three classic STHs, and ivermectin for S. stercoralis (77).

Immune responses to STH infections are broadly similar, characterized primarily by systemic and local type-2 responses (78, 79). In the gut, the “weep and sweep” response predominates, which is defined by increased mucous production and smooth muscle contraction (79). The cytokine response includes early production of IL-25 and IL-33, followed by long-term production of IL-5, IL-13, IL-4, and IL-10 (80). Chronic infection with STHs requires a degree of immune tolerance (characterized primarily by IL-10), allowing the worm to survive but protecting the host from excessive immunopathology. This semi-tolerant state is known as a modified T_H2 response (81).

Generally, STH and schistosomiasis endemicity patterns are similar; however, because schistosomes require the presence of freshwater bodies and snail hosts, their epidemiology is more focal than STHs, which can occur anywhere suitably moist soil and fecal contamination intersect (82). STHs and schistosomiasis are both heavily associated with poor sanitation and are targeted by the World Health Organization (WHO) global Water, Sanitation, and Hygiene (WASH) program and MDA efforts (83). While both diseases are caused by macroparasitic worms, differences in their niches within the host result in differences in the host immune response. The characteristic helminth “weep and sweep” response does not apply to blood vessel-dwelling schistosomes; likewise, egg-related granulomatous immunopathology is not typical of STH infections. Nevertheless, both types of worms induce significant T_H2 responses, albeit in differing contexts, and modulate the immune response toward a regulatory profile (84).

Research into immune responses in Schistosoma-STH co-infections has seen an uptick in recent years, but large gaps in understanding remain. A 2008 review on the topic found several studies on animal models of co-infection as well as epidemiological patterns, but few papers investigated their immune responses (34).

Co-infections with STHs and schistosomes are well established to have different infection burdens than mono-infections (higher or lower, depending on various factors), as elaborated in reviews (7, 34). Within S. mansoni and Strongyloides venezuelensis (a rodent helminth used to model St. stercoralis) co-infections, St. venezuelensis infection burdens differed, as did immune responses in the lungs and small intestines, based on the timing of one infection relative to the other. When mice were simultaneously co-infected with S. mansoni and St. venezuelensis, the infection burden was equal to that of St. venezuelensis mono-infection. However, when infected with S. mansoni prior to St. venezuelensis, mice had significantly lowered St. venezuelensis burdens (up to 92% lower), regardless of whether the secondary infection was 2, 4, or 14 weeks after the first. This suggests that the life stage of the schistosomes may be independent of conferred Strongyloides immunity. Given that schistosome-induced immune responses in mice follow a T_H1-T_H2-regulatory trajectory, it is somewhat surprising that both early and chronic schistosome infections would be protective against Strongyloides. In the lungs and small intestine, the characteristic T_H2 responses of St. venezuelensis infection was not affected by the background Schistosoma infection; St. venezuelensis infection induced local production of IL-4 and IL-5, eosinophilia, and increased serum IgE. The T_H1 and regulatory responses, however, did differ, depending on when the secondary infection occurred. St. venezuelensis co-infection during acute schistosomiasis resulted in lower IFNγ and IL-10 in the lungs and intestines compared to co-infection during chronic schistosomiasis (85).

While Strongyloides burden varied depending on the time of S. mansoni co-infection, St. venezuelensis had no effect on S. mansoni worm burden, regardless of the timing of co-infection. That said, the immune response and pathology in the liver were altered. When compared to Schistosoma-mono-infected mice, those co-infected simultaneously with Strongyloides showed a greater T_H1-skewed cytokine profile in the liver, while those infected 2 weeks after Schistosoma had a greater T_H2-skewed profile. When Strongyloides was introduced 4 weeks after schistosomiasis, cytokine production increased, but there were no discernible changes in profile. Notably, liver granuloma size at 15 weeks post-S. mansoni infection was significantly increased in mice co-infected with St. stercoralis simultaneously, 2 weeks, or 4 weeks after S. mansoni infection compared to S. mansoni-mono-infected mice (10%–15% increase in inflamed liver tissue per field of view). Markers of liver injury were also significantly increased in mice infected simultaneously and those infected with Strongyloides 2 weeks post S. mansoni. In contrast, mice infected with St. venezuelensis during chronic schistosomiasis (14 weeks post S. mansoni infection) had no significant changes in their cytokine profile or liver pathology compared to those which were S. mansoni mono-infected (86). It is possible that the presence of another pathogen during the inflammatory stages of early schistosomiasis exacerbated pathology, whereas the immunoregulatory stages of chronic schistosomiasis were able to prevent changes to pathology. These results highlight the complexity of the immune response to co-infection and how the immune background of the individual can affect their response to additional infectious insults. While it is important to consider the temporal dynamics of co-infection, in human populations, especially in endemic areas, information regarding timing of infection is exceedingly rare. It is also worth noting that it is typical for individuals to be exposed to STHs earlier in life and schistosomes later, as water contact increases through childhood (34), calling into question the translational relevance of the infection pattern applied here.

In addition to changes in worm burdens, co-infections can result in pathology changes. In mice, co-infection with Heligmosomoides polygyrus (model organism for hookworm) and S. mansoni resulted in lower schistosome-induced hepatic egg pathology (7, 87). In contrast, studies investigating the effect of whipworm infection on schistosomiasis egg pathology have found that this co-infection led to significantly increased pathology (7, 88, 89). One recent study compared schistosomiasis in baboons already chronically infected with T. trichiura to those mono-infected with S. mansoni. The authors found that while worm and egg burdens were similar between the groups, the co-infected group had significantly larger liver granulomas; the average size was nearly double that of the mono-infected group. Additionally, RNA sequencing analysis showed enrichment in pathways predictive of liver damage and hepatic injury in the co-infected group compared to the mono-infected group (89). As in the S. mansoni and St. venezuelensis co-infection experiments, these results suggest that even in cases where parasite burden is not influenced by co-infection, changes in pathology should still be considered and may be highly significant.

Naturally, immunomodulatory pathogens like helminths have been shown to change reactivity to antigen, and the same effect can be observed when they co-infect. This has been demonstrated in samples from individuals co-infected with a hookworm infection and either A. lumbricoides or S. mansoni or both (90). Peripheral blood mononuclear cells (PBMCs) from co-infected individuals showed significantly lower TNFα, IFNγ, and CXCL10 responses upon hookworm antigen stimulation compared to those infected with hookworm alone. In contrast, co-infected individuals had higher hookworm-antigen-specific antibody responses (IgG subclasses and IgE). Additionally, there was a strong negative correlation between fecal hookworm egg counts and IL-10 production in mono-infected individuals which was not present in co-infected individuals. Overall, these data suggest that co-infection dampens hookworm-specific T_H1 responses; however, it is impossible to determine whether this effect is due to the addition of A. lumbricoides or S. mansoni as the groups were not separated (90).

Another immune modulation seen in STH and schistosome infection is changes in the level of trefoil factor family proteins (TFF1, 2, and 3), a family of glycoproteins involved with tissue repair at mucosal surfaces (91). In the gut, TFFs are secreted by goblet cells, and TFF2 and TFF3 are most prevalent (91). TFF2 levels were significantly higher in hookworm-mono-infected individuals, especially female participants, compared to endemic and non-endemic controls. This shift was not seen in S. mansoni-mono-infected or in co-infected individuals. Conversely, TFF3 levels were higher in S. mansoni-mono-infected but not hookworm-mono-infected or -co-infected participants. In vitro analysis showed that treatment with recombinant human TFF2, but not TFF3, could suppress an artificially induced high-inflammatory state. Thus, TFF2 may be used in hookworm-induced immunomodulation (91) which may be abrogated during S. mansoni co-infection. This work suggests that TFFs have a role in anti-helminth immunity, but more studies will be needed to fully elucidate that role and how co-infection may change it.

Given the increases of IgE in helminth infections and the links between helminths and allergy (81), another area of investigation is the effect of co-infection on this association. Simultaneous treatment of PZQ and albendazole in a region of Uganda co-endemic for schistosomiasis and hookworm resulted in increased anti-Schistosoma adult worm IgE production which was associated with a reduced susceptibility to S. mansoni reinfection. However, the same immunity was not developed for hookworm (92). In fact, IgE specific for hookworm adult worm antigen and S. mansoni egg antigen remained unchanged or significantly decreased. Yet, despite these decreases, histamine release in response to adult worm antigens of both helminths was found to increase after treatment. Additionally, histamine release in response to environmental allergen house dust mite (HDM) increased after treatment (93). This finding suggests that helminth co-infections may suppress histamine release and, in turn, allergy. This hypothesis was supported when effective treatment of S. mansoni and hookworm led to enhanced levels of HDM Der p1-specific IgE, a risk factor for the development of allergic disorders (94). These studies present preliminary evidence supporting the hygiene hypothesis in hookworm/S. mansoni co-infections; albeit, there are not yet sufficient data to say that co-infection with these two worms is protective against allergy.

STH infections are one of the most common infections worldwide and are prevalent nearly everywhere schistosomiasis occurs. The interactions between these worms are complex and warrant further study. Co-infection with S. mansoni following St. venezuelensis infection resulted in lowered St. venezuelensis burden, but the opposite did not hold true (85, 86). Although the presence of STH infection (St. venezuelensis or hookworm) was not shown to decrease schistosome burden in the studies discussed here, there was a notable decrease in liver pathology observed in co-infections (86, 87). This can be logically attributed to the immunoregulatory effects of STH infection. In addition to infection burden and pathology, co-infection seems to shift cytokine dynamics (90), levels of TFFs (91), and histamine release (92, 93). These observations are preliminary and should be validated in further studies. There is also a significant lack of research into the effects of S. haematobium and S. japonicum co-infection with STHs. It is important to understand the immune responses and pathology changes that occur during these co-infections, given how commonly they co-infect.

PLASMODIUM

Plasmodium spp. are protozoan parasites responsible for malaria. There are five species of Plasmodium which infect humans: notably, Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (35). The WHO estimated 247 million cases of malaria and over 600,000 deaths in 2021 (95). The most common malaria symptom is fever, which occurs primarily in children under the age of 5. Treatment varies depending on the species; however, artemisinin-based combination therapies are the favored choice with over 98% cure rates (35). One vaccine has recently been approved and recommended for malaria prevention in children, RTS,S/AS01, a recombinant vaccine containing the P. falciparum circumsporozoite protein and a hepatitis B surface protein and providing 30% protection from severe disease, although another, R21/Matrix-M, is showing promising results in clinical trials (96).

Over 40 species of the Anopheles mosquito can transmit malaria (35). During a bloodmeal, mosquitoes inject sporozoites into the host which infect liver cells. The sporozoites form a schizont within the liver cells which burst, allowing merozoites to escape and infect erythrocytes. Individuals living in malaria prevalent regions typically undergo a gradual and partial development of immunity over several years, which provides low levels of protection against the disease. This protection is believed to be due to anti-sporozoite and anti-merozoite IgG antibodies (35). Additionally, IFNγ production increases parasite phagocytosis and, thus, increases parasite clearance (97).

Helminth and Plasmodium co-infection is common due to their geographical overlap. Schistosoma and Plasmodium are co-endemic to sub-Saharan Africa, Asia, and South America (98). Varying rates of co-infection have been reported, as high as 34% in sub-Saharan Africa (99) and more recently 2.8%, 8.36%, and 8.7%, in Ethiopia (100), Ghana (101), and Cameroon (102), respectively. Since most studies looked at the prevalence of co-infection in children, it is important to note that the rate of pregnant women co-infected with S. haematobium and P. falciparum was 15.2% in Cameroon (103).

In Cameroon and Uganda, school age children with Schistosoma and Plasmodium co-infections led to reduced Plasmodium parasite burdens and in Cameroon, a reduced level of Schistosoma infection when compared to children with mono-infections (102, 104). It was hypothesized that this was a consequence of the early T_H1 response elicited by schistosomiasis which helped control the Plasmodium infection (104), though it was not determined which infection came first. In most studies, the rate of anemia was higher in co-infected patients compared to Schistosoma or Plasmodium mono-infections (100–103, 105, 106) except in Ghana where moderate levels of anemia only occurred in 5% of co-infected patients compared to schistosomiasis (21.7%)- or malaria (17.8%)-mono-infected patients with no statistical difference in hemoglobin levels between groups (107). In Cameroon, the most common symptoms of Schistosoma and Plasmodium co-infection in children were hematuria, microcytosis, and fever (102). High levels of hematuria were also seen in children in Nigeria where 57.1% of children were infected with S. haematobium and P. falciparum. In this population, 63.8% of co-infected children had hematuria compared to 52.2% of the S. haematobium group and 43.7% of the P. falciparum group (108).

When considering the immunopathology of co-infection, Schistosoma and Plasmodium co-infection led to an increase of anti-Plasmodium (5%–15%) and anti-Schistosoma (6%–22%) IgG, an increase in anti-Plasmodium IgG1 (0.43–0.9 pg/mL), IgG2 (0.25–0.87 pg/mL), and IgG3 (0.80–1.53 pg/mL), an increase in IL-4 (40% for co-infection vs 3.3% for mono-infection), and a decrease in γδ T cells (109–111). It was hypothesized that the co-infected children have a helminth-induced T_H2-skewed immune response which could explain the increase in anti-malaria antibodies, leading to lower P. falciparum parasite densities (110).

In non-human primates, chronic schistosomiasis protected animals from severe P. knowlesi infection, and they had reduced levels of Plasmodium parasite (81.25% vs 25% protection). Interestingly, Schistosoma- and Plasmodium-co-infected animals had lower levels of IFNγ compared to Plasmodium-only infections and compared to PZQ-treated animals. There also appeared to be lower levels of IL-10 and TNFα after P. knowlesi infection in the baboons with schistosomiasis compared to those without (112). In a multi-dose P. knowlesi infection model in baboons with and without prior schistosomiasis infection, anti-P. knowlesi IgG and IgG1 levels and CD4⁺ memory T cells were found to be lower in the co-infected animals compared to those that only had P. knowlesi infections (113). This contradicts the epidemiological data, showing that humans had higher IgG levels when co-infected with schistosomiasis (109, 110). While it is unclear how malaria protection was mediated in this model, monocyte levels were higher in the schistosomiasis- and P. knowlesi-co-infected baboons compared to the P. knowlesi-mono-infected baboons (113).

In C57BL/6 mice infected with S. japonicum and P. berghei, co-infected mice had lower levels of IFNγ but higher levels of IL-4, IL-5, IL-13, and TGFβ when compared to P. berghei single infections. The co-infected mice also had lower levels of splenic CD4⁺ and CD8⁺ T cells but higher levels of T_REG cells than the Plasmodium-only infected group (114). S. mansoni and P. yoelii or P. berghei co-infection in BALB/c, C57BL/6 mice, and CBA/J mice had significantly lower levels of Plasmodium in liver cells of co-infected mice compared to mono-infected mice. Similarly, when mosquitos were allowed to feed on co-infected and Plasmodium-only infected mice, there was less Plasmodium in the mosquitos that fed on mice with S. mansoni infection compared to those that fed on mice without (115). In addition, liver burden protection conferred by schistosomiasis was abolished in IFNγ^−/− and IL-4^−/− mice, suggesting that these cytokines play a protective role in Plasmodium infection despite the reduction of IFNγ in co-infected animals.

Of particular interest is the role co-infection with malaria and schistosomiasis plays in parasite treatment. In Ethiopia, the malaria treatment artemether-lumefantrine, cured all cases of schistosomiasis in malaria-co-infected patients (116). Similarly, in the Democratic Republic of Congo, children co-infected with Plasmodium and S. mansoni were treated with artesunate-amodiaquine; S. mansoni was cured in 74.4% of these children and partially reduced in 22% (117). While it is unclear how these anti-malaria drugs kill schistosomes, both these parasites share certain characteristics such as residing in the blood, hemoglobin digestion (118, 119), and susceptibility to reactive oxygen species (ROS) and calcium signaling disruption (120, 121). These shared features suggest that anti-malaria drugs which act through these mechanisms may also target schistosomes, and therefore, it may be feasible to clear both parasitic infections with a single treatment.

Although there is great variability in the incidence rate of Schistosoma and Plasmodium co-infection, these rates can be as high as 34% (99) and 57.1% (108), making co-infection an important consideration when studying schistosomiasis. Overall, co-infection appears to lead to a decrease in malarial parasite load (102, 104, 115), but an increase in anemia (100–103, 105, 106) is depicted with relevant immunological changes in Fig. 3. The immunopathology of co-infection is more complex where T_H2 responses seem to be favored over T_H1 responses in both humans and mice; however, non-human primate studies show decreases in both T_H1 and T_H2 responses (112, 113). Still, studies show that malaria treatments have been successful in treating co-infections (116, 117). With the development of newly approved malaria vaccines, it will be of interest to determine their effects on co-infections of malaria and schistosomiasis.

Fig 3.

Proposed immunological effects of schistosomiasis and malaria co-infection. In recent epidemiological studies and in mouse co-infection models, schistosomiasis leads to an increase in T_REG cells, an increase in anti-malaria antibodies and in IL-4 (T_H2-skewed response) which appear to reduce the levels of Plasmodium and decrease pathology. However, co-infection increases the risk of anemia. More research must be done to clarify the effects of other aspects of the immune response since they remain unclear.

LEISHMANIA

Leishmania are intracellular protozoan parasites, which cause a range of diseases depending on the species (122). Cutaneous leishmaniasis (CL) is the most common and least severe form of the disease, defined by skin lesions. CL can be caused by a plethora of Leishmania species, including Leishmania major, L. tropica, L. aethiopica, L. mexicana, L. amazonensis, L. braziliensis, L. guyanensis, and more recently described hybrid parasites (122, 123). There is an estimated 700,000–1.2 million new cases of CL globally, per year (122). Visceral leishmaniasis (VL) is considered the most severe form of the disease which is characterized by enlargement of the liver and spleen and causes anemia, internal bleeding, and immunosuppression which can be fatal when untreated. VL is caused by L. donovani and L. infantum with approximately 50,000 cases, annually (122). Despite this, no vaccine has been approved for human leishmaniasis (124, 125). Treatment varies greatly depending on the species and region of the infection, but some options include amphotericin, pentavalent antimonials, miltefosine, paromomycin, and thermotherapy (122).

The Leishmania life cycle begins when a host is bitten by a sandfly (the vector) and is injected with a promastigote, a long-flagellated eukaryotic cell. Injected promastigotes are phagocytized by neutrophils and macrophages and then transform into non-flagellated, circular cells, called amastigotes. Amastigotes replicate within the macrophage and go on to infect other macrophages. The life cycle is completed when a sandfly takes a bloodmeal from an infected host, and within the sandfly, amastigotes transform back into promastigotes (126). Depending on the species, Leishmania can have a variety of animal reservoirs, except for L. donovani which only infects humans (122).

Leishmania infection can be successfully cleared by a T_H1 immune response where IFNγ and TNFα elicit nitric oxide (NO) and ROS, both of which are released in infected macrophages, killing Leishmania amastigotes (127). This T_H1 response can elicit lifelong protection against Leishmania re-infection following treatment or asymptomatic infections (128).

Since Schistosoma and Leishmania are co-endemic to many countries within Africa (e.g., Sudan), South America (e.g., Brazil), the Middle East, and Asia (98, 122), it is important to consider the potential of co-infection. Surprisingly, few cases of co-infection have been described.

In Brazil, the occurrence of S. mansoni and CL co-infection is 16.7% and 43.2% depending on the region, and patients with a history of CL were two times more likely to be infected with S. mansoni when compared with those who did not have a history of CL (129). S. mansoni infection increased CL patient healing time after antimony treatment despite co-infected patients having smaller lesions (280 mm²) than CL-only infected patients (400 mm²). This could be due to a T_H2-skewed response shown by elevated levels of IgE (1,578 vs 427 IU/mL) and IL-5 (364 vs 184 pg/mL) in co-infected patients (129). Furthermore, Leishmania appeared to alter immune responses to S. mansoni since co-infected patients had lower levels or occurrence of eosinophilia (34% vs 51%), CCL17 (233.5L vs 341.0 pg/mL), and IL-17 (2% vs 18.5%), factors (129) that are usually high in S. mansoni infection (127, 130, 131). Since both population-based studies were conducted in Brazil, it would be important to conduct research in other geographical locations where these parasites are endemic to see if these phenomena are transferrable.

In VL cases, gastrointestinal pathology is rare but may be possible in VL and S. mansoni co-infection (122). A case report of a patient with visceral leishmaniasis, anti-leishmanial antibodies, and chronic diarrhea described a failure to resolve the diarrheal disease after amphotericin B treatment and resolution of visceral disease. S. mansoni eggs were identified in the patient’s stool, and following PZQ treatment and a second round of amphotericin B, the diarrhea is fully resolved (132). Similarly, another patient presenting with sporadic diarrhea tested positive for S. mansoni and Leishmania. However, instead of visceral disease, this patient presented with cutaneous lesions on the abdomen and elbow. Praziquantel and meglumine antimoniate were able to resolve both infections (133).

Experimental mouse models of Schistosoma and Leishmania examined the immunopathology of co-infection. When mice were infected with S. mansoni followed by L. major, lesions were larger, and CL resolution was delayed compared to L. major infection alone (134). This contrasts with population-based studies in humans which showed smaller lesions in co-infected individuals yet a similar increased healing time (129). This delayed healing may be a consequence of the decrease in IFNγ, NO, and TNFα in the popliteal lymph nodes of co-infected mice vs L. major-only infected mice, suggesting an impaired T_H1 response resulting in decreased macrophage killing of amastigotes. In parallel, IL-4 was upregulated in co-infected mice which suggests an upregulated T_H2 response (134). Similarly, when mice were infected with L. donovani and S. mansoni, leishmanial parasite burden increased over time (2720 LDU; Leishman-Donovan units) when compared to L. donovani single infection (82 LDU) (135). Just like the L. major co-infections (134), L. donovani-co-infected mice showed elevated IL-4 compared to singularly infected mice. They also showed increased IL-10 and decreased IFNγ, but these levels equated over time. Moreover, the S. mansoni granuloma appeared to be a favorable growth environment for L. donovani in mice, demonstrated by increased levels of amastigotes and decreased expression of NO in co-infected mice compared to mice infected with L. donovani alone (135).

Since disease pathology was altered in Schistosoma and Leishmania co-infection, it is important to consider if response to treatment is also altered. In BALB/c mice co-infected with S. mansoni and L. major, both lesion size and parasite burden had a greater reduction in mice that were treated with antimonials and PZQ compared to treatment with only one of the two drugs (136). Although there have been no signs of drug interaction when using combined chemotherapy in mice, some liver toxicity was noted at the beginning of treatment (136). Toxicity of combined chemotherapies should be further examined in humans.

Unfortunately, little is known about the rate of Schistosoma and Leishmania co-infection except in Brazil, where rates are estimated to be as high as 43.2% depending on the region (129). It is not known if these rates are representative of other countries where co-infection occurs. An additional challenge in surveillance is the difference in disease presentation, where Schistosoma co-infection with VL or CL can present as gastrointestinal disease (132, 133). Currently, it is not routine to screen for either of these parasites following gastrointestinal symptoms, so infections exhibiting these symptoms may go undiagnosed. In humans, CL lesions are smaller with faster healing times, and the immune response is predominantly characterized by an increase in a T_H2 profile (127, 129). While mouse co-infection studies demonstrate predominant T_H2 responses, T_H1 responses are reduced, and lesion sizes, healing time, and parasitemia are increased (134, 135). This phenomenon has been discussed in a recent review (137). Perhaps, the mouse model does not adequately represent Schistosoma and Leishmania co-infection pathology in humans, and another model should be considered (e.g., hamsters). Nevertheless, mouse models remain an important tool since both humans and mice display strong T_H2 responses following co-infection.

TRYPANOSOMA

Trypanosomiasis is often caused by one of two infecting species: Trypanosoma brucei responsible for African trypanosomiasis and T. cruzi responsible for American trypanosomiasis, both of which are also neglected tropical diseases (138).

African trypanosomiasis is primarily found in sub-Saharan Africa and is transmitted through the bite of a tsetse fly. Two main strains dominate infections of human African trypanosomiasis: T. b. gambiense and T. b. rhodesiense. These parasites infect the bloodstream and lymphatic system, and spread to the central nervous system, causing neurological symptoms. T. b. gambiense has been targeted by the WHO for total interruption of transmission by 2030 (139). Unfortunately, elimination is dependent on active case detection which is not feasible for T. b. rhodesiense due to its large animal reservoir and zoonotic nature (140).

American trypanosomiasis, or Chagas disease, is mostly found in Central and South America and is spread through the feces of reduviid bugs, also known as “kissing bugs.” The parasite enters the body through bite wounds or mucosal membranes and invades various tissues, notably the heart, and digestive and nervous systems. In chronic stages of Chagas disease, individuals may develop cardiac or gastrointestinal pathologies due to inflammation and tissue damage in response to the presence of T. cruzi nests, which, if left untreated, can be life-threatening (141).

Together, T. brucei and T. cruzi affect approximately 80 million individuals worldwide (142, 143), often in geographical locations where schistosomiasis is also present. Co-infections of these parasites have been reviewed previously (7), citing that in albino mouse models, Trypanosoma tends to suppress infection with S. mansoni/S. bovis (resulting in lower fecal egg counts per worm pair and reduced frequencies and diameters of egg granulomas) regardless of the order of infection. However, there are contrary data demonstrating co-infections present with increased splenomegaly and higher mortality than controls, with higher parasitemia of T. cruzi (144).

In correspondence with the latter data, a group from Brazil published work on T. cruzi infection 4 months post infection with S. mansoni (approximately 2 months into chronic infection) (145). This group found that when co-infected, animals experienced higher peak parasitemia as well as mean parasitemia compared to animals infected with only T. cruzi. In this study, co-infected animals presented reduced levels of IFNγ but higher levels of IL-10 compared to T. cruzi mono-infected animals. These findings suggest that S. mansoni infection may result in a reduced ability to mount a T. cruzi-protective T_H1 response.

Furthermore, co-infected animals displayed a higher number of hepatic granulomas with marked confluence, higher cellularity, and lower fibrosis than animals infected with only S. mansoni, where granulomas were diffuse, well delimited, with low cellularity and higher collagen production. As granulomas mature, they become fibrotic to trap Schistosoma eggs and protect the host from hepatotoxins such as omega-1 (146, 147). This is especially important in the liver where eggs are not able to egress through the feces and are embedded in the tissue. Granulomas found in co-infected animals were more exudative-productive than they were fibrotic, which was inverse in animals which were only infected with schistosomiasis. This may show that when T. cruzi was present, there was a slowed progression of fibrosis around Schistosoma eggs, possibly resulting in a higher release of hepatotoxins.

The limited body of research surrounding trypanosomiasis and schistosomiasis co-infections focuses on T. cruzi and lacks information on T. brucei. Overall, the pathology resulting from both parasites together is controversial and differs in the literature. While early data demonstrate that co-infection with Trypanosoma may lead to protection from Schistosoma (148, 149), recent reports demonstrate that co-infection with the protozoan parasite may lead to increased liver pathology in schistosomiasis and increased Trypanosoma parasitemia (144, 145). One contribution to the discrepancies within results may be explained by the time at which animals were challenged which varied between papers. Trypanosoma-induced protection from Schistosoma may be temporal; protective effects seem to become weaker as the time between co-infections becomes longer (150). Furthermore, each study administered parasites with varying routes. Generally, 1,000–6,600 trypanosomes were administered intraperitoneally, and 25–40 schistosomes were given subcutaneously or percutaneously depending on the study; each of these variables can affect the data obtained. There is a lot of information yet to be gleaned from trypanosomiasis and schistosomiasis co-infection research. Since the data we have now come from animals, this leaves a large gap of knowledge in healthcare and epidemiological data. This underscores the need for further research in clinical settings to understand these co-infections within a human context.

TOXOPLASMA

Toxoplasmosis is caused by the obligate intracellular parasite Toxoplasma gondii, and although it can be found globally, it is more common in warmer, humid climates and in areas with poor sanitation (151). While only 10% of North Americans may have been exposed to T. gondii, in areas endemic for schistosomiasis and Europe, up to 60% of the population may have encountered this parasite (151). Although infection rates vary and European infections are often asymptomatic in immunocompetent individuals, toxoplasmosis presents with more severe manifestations in those who are pregnant and/or immunocompromised and those living in South America (152, 153). After acute infection, characterized by general flu-like symptoms, toxoplasmosis evolves into a chronic phase where parasites encyst into the brain and other organs in latent form. In cases of immunosuppression, these parasites can reactivate and result in pulmonary (154), cerebral (155), or ocular disease (156); infections in pregnant individuals may cause severe damage to the fetus, and congenital toxoplasmosis (vertical transmission) in children is likely to progress into clinical toxoplasmosis (155, 157).

One of the primary control cytokines expressed against T. gondii is IL-12, released upon parasite recognition by DCs, macrophages, and monocytes. In mice, this expansion is driven by parasite profilin recognition by toll-like receptors 11 and 12 (158, 159). While humoral immunity and antibody generating B-cells have been shown, in part, to mediate protection from toxoplasmosis (160, 161), type-1 immune effectors, such as IFNγ, are key contributors to parasite control and resistance (162).

Toxoplasma gondii is the most prevalent in Africa and parts of South America (163), and although its endemicity overlaps with Schistosoma in a broad range of locales, reports of co-infection in humans are indirect and limited to Tanzania (164, 165), Egypt (166, 167), and the Hunan province of China (168).

The earliest works of Schistosoma and Toxoplasma co-infection were conducted with S. mansoni in mouse models (169, 170) followed by the introduction of T. gondii. While effects were minimal when Toxoplasma preceded Schistosoma infections, both studies demonstrated that when mice were first infected with Schistosoma and then Toxoplasma, their mortality increased significantly. This was accompanied by increased levels of total IgE and TNFα, with a decrease in IFNγ and NO production. Recently, the increased severity of disease progression in co-infection was supported, again showing that mortality was increased when both parasitic infections were present (171).

Interestingly, small intestine pathology typical of Toxoplasma infection was ameliorated in mice that were first infected with Schistosoma. This includes histological changes such as inflammatory infiltration of the lamina propria, blunting of the villi, abnormal architecture, and areas of epithelial disruption. Of note, Schistosoma-co-infected animals displayed preserved goblet and Paneth cells, alongside a reduction of inflammatory cytokines. Ileal tissues also showed a decrease in expression of mRNA transcripts for IL-1β and nitric oxide synthase 2 and a decrease in activation of NFκB and p38 MAPK signaling (necessary for downstream cytokine production).

While T. gondii pathology was ameliorated in the intestines, Schistosoma co-infection became detrimental within the liver, which likely contributed to the increased mortality. Intracellular infection with Toxoplasma suppressed the S. mansoni-induced T_H2 response necessary to prevent the release of Schistosoma egg hepatotoxins. Although visually clearer, with fewer Schistosoma-induced granulomatous formation, microscopic analysis showed that co-infected animals exhibited hepatic coagulative necrosis with extensive hepatocyte vacuolization, in support of previous work (169). Livers in these co-infected mice also showed fatty acid changes, with increased lipids and variations in metabolism (171).

Since IL-12 plays a significant role in toxoplasmosis control, one group explored its contributions to S. mansoni and Toxoplasma co-infections using IL-12 knockout mice (172). They found that IL-12-deficient mice did not share the same mortality as their wild-type counterparts when co-infected with both parasites. In fact, not only did they live longer, but splenocytes from these animals expressed lower levels of TNFα, IFNγ, NO, and increased (more than twofold) levels of IL-5, and IL-10. Further evidence that IL-12 contributes to the detriment of co-infected animals is that IL-12^−/− animals did not display the same severe coagulative necrosis and cytoplasmic vacuolization seen in wild-type animals as the hepatic parenchyma and architecture were mostly preserved.

Together, the data suggest that the introduction of toxoplasmosis into an infection of schistosomiasis induces an immune shift away from typical T_H2 responses, resulting in worsened schistosomiasis outcomes but ameliorated toxoplasmosis pathology in the small intestine (171). Knockout models of infection showed that IL-12 is a pertinent contributor to the pathology witnessed in co-infected animals, as in its absence animals lived longer and displayed a stronger T_H2 profile (172). Still, the order of infection may play a significant role as studies demonstrate minimal changes when toxoplasmosis infection precedes schistosomiasis (169, 170). Like trypanosomiasis, to advance the field of toxoplasmosis-schistosomiasis co-infections, further clinical and epidemiological research is essential, with a focus on understanding the molecular mechanisms underlying these co-infections in human populations. This could inform better strategies for parasitic management and control in co-endemic areas.

INTESTINAL PROTOZOA

There are a variety of intestinal protozoa that infect humans causing infections ranging from asymptomatic colonization to severe disease. The most common pathogenic intestinal protozoa are Giardia duodenalis (syn. G. lamblia, G. intestinalis), Cryptosporidium spp. (typically C. hominis and C. parvum), and Entamoeba histolytica (173–175). The classic manifestation of intestinal protozoa infection is diarrhea. Intestinal protozoa are spread worldwide, but typically, more infections occur in tropical climates and/or areas where access to sanitation is poor. Transmission occurs through the fecal-oral route, often involving consumption of contaminated food and water (176–178). Both G. duodenalis and Cryptosporidium cause malabsorption and failure to thrive (179), and co-infections with the two protozoa are common (180). Many species of Entamoeba infect humans (176), but the majority are considered non-pathogenic. E. histolytica is primarily responsible for invasive disease, although only 10% of E. histolytica infections cause illness (181). Symptoms of amoebiasis include dysentery (sometimes severe) and extraintestinal symptoms, particularly amoebic liver abscess (182).

As all intestinal protozoa colonize the gut, there are some broad similarities in the immune responses they elicit. The intestinal epithelium and mucosa make up an important physical barrier, and breaching of this barrier is typically what leads to pathology. Gut mucosal immunity, such as IgA secretion, is important in intestinal protozoan immunity. Once the intestinal barrier is damaged by intestinal protozoan invasion, alarmins are secreted from intestinal epithelial cells, and innate immune cells are recruited to the site of damage. Cryptosporidium and E. histolytica infections drive a T_H1-type response, with IFNγ having a protective role in both infections. G. duodenalis, in contrast, induces a T_H17-skewed response, characterized by high levels of IL-17 (183, 184). IL-17 likely also plays a role in E. histolytica control; IL-4 and TNFα are associated with disease progression (185).

Intestinal protozoan infections occur worldwide, but as their incidence is increased in warm areas and locations with poor sanitation, there is significant overlap between them and schistosome infections. Co-infections of Schistosoma spp. and intestinal protozoa have been recorded in a variety of contexts (186–190), but information on the immune response in co-infection remains limited. One prevalence study in North Samar, The Philippines, found that co-infections with S. japonicum and intestinal protozoa were highly prevalent. The co-infection rates with S. japonicum were 17.7% (for Cryptosporidium spp.), 14.6% (for G. duodenalis), and 9.9% (for E. histolytica). High rates of co-infection with a fourth intestinal protozoan, Blastocystis (44.9%), were also observed (189). There was a significant correlation between egg patent schistosomiasis and giardiasis in a community around Lake Albert in Uganda; however, specific rates of co-infection of Schistosoma spp. and G. duodenalis were not reported (188). Some studies outlined in a review found that co-infection with E. histolytica and Schistosoma spp. resulted in higher Entamoeba burdens and worsened morbidity in animal models and humans (7). A recent case report outlined the effects of co-infection with S. mansoni and E. histolytica in a 12-year-old boy from Ethiopia. After presenting to the hospital with bloody diarrhea, vomiting, weight loss, and fever, the patient was examined and diagnosed with ulcerative colitis and fulminant hepatitis due to his infections. The authors suggest that both infections contributed to the intestinal condition, but only S. mansoni to the hepatitis due to the lack of a liver abscess. The patient also showed signs of renal failure, but whether that was due to these infections was unclear. After treatment with PZQ and prednisone, the patient made a full recovery. This case highlights the need to better understand the pathology of intestinal protozoa and Schistosoma spp. co-infections, particularly in the context of bowel disease (190).

Unfortunately, more comprehensive research is lacking, and little to no information is available on the effects of co-infection with other intestinal protozoa on the immune response. It is important to better understand intestinal protozoa and schistosome co-infections as their pathologies and immune responses can be significantly altered by co-infection. Intestinal protozoa cause damage to the gut epithelium, which could have consequences for schistosome egg deposition and intestinal symptoms, given the proximity of where these pathogens reside. Likewise, the immune dampening seen in chronic schistosomiasis could influence the body’s ability to control intestinal protozoan infections. It is also important to consider the shared conditions that lead to schistosome and intestinal protozoan infections, namely, contamination of water with fecal matter and/or urine. WASH efforts will affect both schistosome and intestinal protozoan infection rates (191), and further integration of the multi-parasite landscape into control efforts will likely be beneficial for those at risk of infection.

MYCOBACTERIUM

Mycobacterium is a genus of bacteria comprising many species which cause disease in humans and animals. Arguably, the most prominent species of Mycobacterium is M. tuberculosis (Mtb). Mtb causes tuberculosis in humans and often affects the lungs as it is commonly spread through aerosols and respiratory droplets (192). Despite being a preventable and curable disease, TB infects 10 million people per year and kills 1.5 million (193).

About a quarter of the world has been infected with Mtb, though most will not develop disease, and some will even clear infection. Upon infection, Mtb may develop into active TB or latent TB (LTB), differentiated by the presence of symptoms and the ability to transmit infection to others. Although the immunological states corresponding to these various disease outcomes have yet to be elucidated, it has been shown that CD4+ T cell responses are important contributors of protection (194), especially those expressing type-1 effectors such as IFNγ (195).

This bacterium is present globally, though most individuals who develop severe disease live in low- to middle-income countries. According to the WHO, about half of all people with TB can be found in eight countries: Bangladesh, China, India, Indonesia, Nigeria, Pakistan, The Philippines, and South Africa (193). Of these countries, all except Bangladesh and Pakistan are endemic for schistosomiasis. Although S. mansoni has been shown to be an independent risk factor for active TB in Tanzania (196, 197), the broad impact of these infections when present together remains under-investigated.

For over 100 years, the bacille Calmette-Guérin (BCG) vaccine has been used to control Mtb (198). BCG is a live attenuated Mycobacterium bovis strain, and as such, BCG immunization and S. mansoni infection can be used as a model for Mycobacterium spp. and schistosomiasis co-infection. In mice infected with S. mansoni, it was found that there was an impaired control of BCG as colony-forming unit (cfu) counts were significantly higher in the lung, liver, and spleens of BCG immunized animals. Furthermore, splenocytes from these animals showed lower proliferation and expression of IFNγ than those which were solely immunized with BCG (199). When this model was extended to include Mtb infection, previous infection with S. mansoni decreased the protection offered by BCG. Not only did S. mansoni infection lead to increased cfu of Mtb in the lungs and liver, but it also resulted in a lower expression of both IFNγ and NO from restimulated spleen lymphocytes. This was accompanied by an increase in tissue damage, as lungs presented with increased cellular recruitment, less air spaces, and less organized granulomas which were diffuse without sharp demarcation from surrounding tissue (200). When Mtb lung granulomas are disorganized, B cell follicles are not well formed, and neutrophils lead to inflammation and damage (201), in contrast to Mtb lung granulomas containing distinct B cell follicles with T cells and macrophages, which are protective to surrounding tissue (202). While BCG is a useful tool to model Mtb infection, it has limitations since it is a different species, and it is attenuated. Still, the BCG data were supported years later in an animal model consisting solely of S. mansoni and Mtb. Monin et al. found that S. mansoni co-infection promoted lung fibrosis and inflammation in Mtb infection and altered the composition of Mtb granulomas (203). In co-infected animals, lung granulomas were found to be both type 2 (containing high arginase-1-expressing macrophages) and type 1 [containing inducible nitric oxide synthase (iNOS)-expressing macrophages] near each other, whereas animals infected with Mtb alone only exhibited type 1 granulomas. Arginase-1 (Arg-1) is a cytosolic enzyme, typically found in the liver, which hydrolyzes L-arginine during the urea cycle (204). In this context, Arg-1, from non-classically activated macrophages, competes with iNOS for L-arginine, limiting its ability to produce NO (205). Lungs from co-infected animals also were high in type 2 effectors, IL-4 and IL-13, matrix metalloproteases (MMP13), and neutrophil-produced myeloproteases. Interestingly, TB severity was reversed when co-infected animals were treated with an anthelmintic, suggesting that the presence of living adult worms contributes to an increased susceptibility to Mtb (203). In fact, when humans co-infected with helminths (Strongyloides, S. mansoni, and both) and LTB were treated with an anthelmintic, their restimulated PBMCs had lower frequencies of T_REG cells and a rescue of Mtb-specific CD4+IFNγ+ T cells compared to before treatment (206).

Human co-infections of Mtb and schistosomiasis have recently been reviewed (37). Briefly, this systematic review demonstrated that S. mansoni impaired the immune response to Mtb and supported the hypothesis that infection with schistosomiasis can lead to a detriment of TB immunity, pushing LTB into reactivation (37). A study out of Switzerland showed that specifically S. mansoni, and not other helminths, was associated with clinical presentation among TB patients in Tanzania (196). Notably, when individuals were co-infected they were found to have less bacteria in their sputum, a finding which was also present in severely immunosuppressed HIV-positive individuals (207), inferring infection may be disseminated and extrapulmonary. This reduction in bacterial control could be attributed to immunomodulation from Schistosoma antigens. S. mansoni SEA has been shown to reduce the frequency of CD4+ T cells expressing IFNγ and TNFα from naïve human PBMCs stimulated with Mtb antigens 6-kDa early secretory antigenic target (ESAT-6) and 10-kDa culture filtrate protein (CFP-10) (208), perhaps as a result of schistosomiasis-dependent epigenetic IFNγ DNA methylation (209). Mtb-specific CD4+ T cell polyfunctional expression of TNFα, IL-2, and IFNγ has been associated with asymptomatic control of infection (210). When first exposed to SEA, CD4+ T cells stimulated with ESAT-6 and CFP-10 were less capable of doubly expressing IFNγ and TNFα, which made up 55.8% of the CD4+ T cell response from non-SEA-exposed cells (208). Schistosoma, and specifically SEA, are known inducers of T_H2 immune responses which have been shown to impair TB immunity (211, 212).

However, when naïve human PBMCs (213) and monocyte-derived macrophages (214) were primed with SEA in vitro, they exhibited improved control of intracellular Mtb. Furthermore, Mtb-specific type 1 CD4+ T cells were maintained in a Kenyan cohort of S. mansoni- and Mtb-co-infected individuals. Curiously, these cells were found to be T_H2 lineage cells (CCR4+) capable of expressing T_H1 cytokines IFNγ, TNFα, and IL-2 (215), although further research is necessary to determine whether these polyfunctional CD4+ T cells were a by-product of schistosomiasis T_H2 immunity. Separately, the role of monocytes (216) and TGFβ-producing T_REG cells (217) in S. mansoni and active TB co-infection have also been investigated. Despite these data, it is still unclear why TB outcomes are worsened in schistosomiasis-co-infected individuals.

Conversely, there are limited data describing the influence of Mtb on outcomes of schistosomiasis, despite the bacterium’s ability to alter immune responses to Schistosoma antigens. PBMCs were drawn from Kenyan individuals and stimulated with S. mansoni soluble worm antigen preparation (SWAP). T cell cytokine production to SWAP was found to be dominated by γδ T cell-expressed IFNγ and TNFα. When cases of active TB were assessed, there was a significant decrease in the amount of responding γδ T cells and an increase in their expression of IL-4 (218). While interesting, it has yet to be elucidated what effect these immune changes may have on schistosomiasis.

Although the immunological effects of schistosomiasis on tuberculosis are unclear, the consensus suggests that helminth-induced T_H2 responses impair T_H1 effectors necessary for Mtb control as summarized in Fig. 4. Schistosomiasis may even increase T_REG responses which, with T_H2 immunity, hinder IFNγ and T_H1-mediated protection from TB. Mtb, on the other hand, has demonstrated the ability to dampen γδ T cell responses to Schistosoma antigens (216, 218). Although most of the literature around Mycobacterium and Schistosoma is composed of Mtb research, recent publications have exposed the importance of schistosomiasis on Mycobacterium leprae, supporting the hypothesis that helminth infections may influence the transmission and risk of active leprosy (219–221). More work is needed to elucidate whether the same mechanisms between schistosomiasis and Mtb could be affecting the pathobiology of M. leprae.

Fig 4.

Proposed immunological effects of schistosomiasis and tuberculosis co-infection. In co-infections of schistosomiasis and tuberculosis, the helminth promotes type 2 responses and type 2 granuloma formation, IL-4 expression, and T_REG responses which may lead to worsened TB outcomes. Research suggests that schistosomiasis reduces CD4+ T cell IFNγ responses crucial for tuberculosis immunity, while tuberculosis reduces helminth-specific γδ T cell responses.

SALMONELLA

Transmitted through the ingestion of contaminated food or water, infections of Salmonella can be found globally. Salmonella is responsible for 180 million cases of diarrheal illnesses that occur yearly, representing 9% of total diarrheal cases. Despite this number being lower than the etiologies of diarrheal disease tracing back to other pathogens (e.g., norovirus, enterotoxigenic Escherichia coli, Shigella spp., and Giardia spp.), a disproportionate number of deaths can be attributed to Salmonella (41% of all diarrheal disease-associated deaths) (222). This genus comprises various species with diverse degrees of severity but is best known for S. enterica subtypes Typhi and Paratyphi causing typhoid and paratyphoid fevers, respectively (223), as well as invasive non-typhoidal S. Typhimurium (iNTS) (224). These species are not evenly distributed around the globe as iNTS is found in Africa, while typhoidal serotypes (Typhi and Paratyphi A) are more commonly found in Southeast Asia (222); both of which are regions endemic for schistosomiasis.

Salmonella are rod-shaped gram-negative bacteria, and despite their ability to live extracellularly, most associated pathology comes from their intracellular life cycle (225). Most manifestations of disease are self-limiting; however, severity depends on serotype involved and the health status of the host. In general, children, the elderly, and immunocompromised individuals are more at risk of infection with Salmonella than healthy individuals (226). In human infections, Salmonella typically presents in four manifestations: enteric fever, gastroenteritis, bacteremia, and chronic carrier state (227).

S. enterica possesses several virulence factors which cause the bacterium to not only activate the immune system but allow it to resist and evade it. Using innate immune cells as a reservoir, Salmonella spp. are capable of invading macrophages and growing and persisting within them. In addition to prevention by vaccination (228), salmonellosis can be treated with oral fluids and antibiotics for those who are immunocompromised (229). Keys of protection from Salmonella include humoral and cellular immunity (230), some cytokines including IL-6, IL-17 (231), and IFNγ (232), as well as bacterial control via the microbiome (233).

The pathogenicity of Salmonella during infections of schistosomiasis has been reviewed recently within the context of the microbiota (234). During cases of co-infection, disease manifests as prolonged fever and hepatosplenomegaly, alongside chronic septicemic salmonellosis (235). Human reports of schistosomiasis and Salmonella co-infections have been seen in Egypt (236, 237), Ethiopia (238), Gabon (239), the Democratic Republic of Congo (240), and Tanzania (241). As early as 1978, it was shown that patients experiencing co-infections of schistosomiasis and Salmonella presented with renal problems (237), and others with prolonged bacterial infection exacerbated pre-existing schistosomal glomerulopathy (242, 243). Interestingly, due to schistosomiasis worms harboring Salmonella bacteria within their intestines and tegument (234, 244, 245), Salmonella-targeting antibiotics became less effective (246). Patients often did not respond to antibiotic treatment, presenting with recurrent fever, until anthelmintics were administered (235, 239, 246).

Multiple studies have demonstrated enhanced colonization of Salmonella spp. in animals infected with Schistosoma spp. (235, 247–249). This effect could be seen in early mouse work where macrophages from S. mansoni-infected mice were less capable of killing S. Typhimurium (250, 251). When mice were injected with S. mansoni eggs, S. Typhimurium led to increased inflammation in the gut lumen (248), and in mice chronically infected with S. mansoni, S. Typhimurium co-infection worsened liver injuries (increased expression of inflammasome and apoptotic proteins) and shifted egg responses from protective granulomas to congested and necrotic (249). This co-infection altered the immune landscape within mice from profibrogenic T_H2 responses to anti-fibrotic T_H1 responses, paralleled with a decrease in IL-4 and IL-5, and increased IL-10, IFNγ, and IL-2. Co-infected animals not only exhibited compounded liver pathology but also increased bacterial loads (248). Additionally, hamster studies showed that S. mansoni and S. Paratyphi A co-infection led to increased mortality (252). Curiously, despite this exacerbation of salmonellosis, mice co-infected with intestinal schistosomiasis exhibited lower worm and egg burdens. S. japonicum and S. Typhimurium co-infection resulted in lower burdens of Schistosoma worms and eggs, than S. japonicum mono-infection. This was accompanied by an increased expression of IFNγ and a decreased expression of IL-4 in the serum showing systemic shifts in immune response (253). Even in a murine co-infection model of S. mansoni and S. Typhimurium, it was observed that co-infected mice exhibited a significant reduction in hepatic eggs compared to those infected with S. mansoni alone (249).

While touched on here, Salmonella and Schistosoma co-infections are complex and understudied, occurring primarily in regions of Africa. Together, these infections lead to prolonged fever, hepatosplenomegaly (235), and unique challenges in treatment due to Salmonella habitation within schistosomiasis worms (234, 244, 245). Although research suggests altered immune responses and reduced Schistosoma parasite burden in co-infected animals, mortality levels and salmonellosis pathology increased. Further studies are needed to elucidate the mechanisms, clinical impact, and potential therapeutic strategies for these co-infections in human populations.

URINARY TRACT INFECTION-CAUSING AGENTS

Urinary tract infections (UTIs) are commonplace worldwide. In fact, more than 50% of all females will experience a UTI at some point in their lives (254). Despite the predisposition of young females to UTIs, there is a significant population of males who experience UTIs (254); UTI prevalence in elderly males and females is similar (255). A myriad of pathogens (mostly bacterial, however, also protozoan and fungal) can cause UTIs, resulting in benign illnesses to serious complications such as sepsis and re-current infection (254).

Due to their global prevalence, UTIs can easily be found in locations endemic for schistosomiasis (256) and have been reported as co-infections in Cameroon (257), Ghana (48), Niger (258), and Nigeria (259), to name a few. Since symptoms of schistosomiasis and UTIs are similar, clinicians sometimes misdiagnose and mistreat infected individuals (260, 261). Most reported cases of dual infection involve S. haematobium, or urinary schistosomiasis; however, cases of S. mansoni and UTIs have also been described (262–266).

Interestingly, while females are more commonly infected with UTIs, field data demonstrate that males are more often infected with S. haematobium (267–269). When both UTIs and schistosomiasis data were compared together, it was found that co-infection in Nigeria was age and gender dependent, with a higher incidence observed in young males (270). Furthermore, most groups conclude that S. haematobium (259, 262, 265, 271–277) and S. mansoni (264, 265, 276) infections increased the incidence of concomitant UTIs. Two groups declared no significant association between S. haematobium and concurrent infection with urinary pathogens (258, 278), though it was found that co-infections with both significantly increased from 0.42% to 7.712% when moving from the dry to rainy season (278).

In schistosomiasis-positive individuals, the most common pathogen infecting the urinary tract was Escherichia coli, though groups also found significant amounts of Klebsiella spp., Staphylococcus aureus, Staphylococcus saprophyticus, Proteus vulgarius, Pseudomonas aeruginosa, Streptococcus spp., and Candida albicans (262, 267, 269, 272, 279) in urine specimens. Trichomonas vaginalis (269, 280, 281), Neisseria gonorrhoeae (281), and Salmonella Paratyphi A (282) have also been reported to infect the urinary tract of individuals with schistosomiasis.

Some have postulated that infection with schistosomiasis poses a risk factor for UTIs due to egg spines causing damage to urinary tissues, providing bacterial entry sites and blood which acts as a bacterial-culturing medium (283, 284). Animal studies using models of co-infection demonstrate that S. haematobium eggs increase susceptibility to uropathogenic E. coli bacteriuria in BALB/c mice due to an increased expression of IL-4 (285) and a reduction of invariant natural killer (NK) T cell-mediated bacterial clearing (286). Additionally, administration of S. haematobium IPSE (an egg-derived protein), despite showing no changes in bacterial cfu, reduced anti-microbial peptides in the bladder and may work in concert with IL-4 to promote the establishment of bacterial infection (287).

UTIs are a widespread issue co-occurring often with schistosomiasis in many African countries. These co-infections are challenging to diagnose due to their similarity in symptom manifestation (260, 261). S. haematobium and S. mansoni are linked to increased UTI risk (259, 262, 264, 265, 270–277), potentially due to parasite damage to host tissue and parasite impact on the immune system, especially in young males (270). Preclinical studies support this hypothesis, showing that schistosomiasis can make animals more susceptible to uropathogenic E. coli infections (285, 286). Given S. haematobium is associated with genital schistosomiasis (48–50), and the urinary tract and genitals are in proximity, UTI co-infections within this context should also be considered. Further research would help our understanding of the mechanisms by which these infections interplay to develop effective strategies for diagnosis and treatment in co-endemic regions.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2

Unlike most bacteria, viruses cannot replicate outside of living cells; the survival of a virus in nature depends on maintaining serial infections (i.e., a chain of transmission; causing disease is neither required nor necessarily beneficial) (288). Still, viral infections can have devastating impacts on the lives and livelihoods of individuals around the globe; for example, coronavirus disease 2019 (COVID-19) alone has led to more than 6.9 million deaths to date (289, 290).

COVID-19 is a respiratory disease that has had devastating impacts worldwide since its declaration as a pandemic by the WHO and has been described as the worst epidemic of the century (291, 292). With over 500 million confirmed COVID-19 cases, the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a rapidly expanding genealogy that now warrants classification of at least 13 variants. Moreover, this virus appears to be becoming endemic, with mutations in the N-terminus and receptor-binding region, including p.Glu484Lys which can be found in the most dangerous variants (293). Variants of concern include Alpha, Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529), with Delta and Omicron being the most severe (294). Since the start of the outbreak, many studies have shown a dramatic increase in COVID-19 in low- to middle-income countries compared to developed countries with better infrastructures and health policies (295). Other factors and various socioeconomic indicators, including gross domestic product per capita, human development index, and differences in the timing of disease onset, have been used to explain geographical differences in the burden of COVID-19 (296, 297).

Neutralizing antibodies have typically been the gold standard of efficacy for viral clearance; however, evidence is growing that CD8+ T cell responses and type-1 immunity are important for SARS-CoV-2 viral clearance, especially in breakthrough infections (298–300). Thus, the immunomodulatory effects caused by schistosomes are a double-edged sword as they may protect the host from the detrimental inflammatory consequences of COVID-19 or support viral infection (301).

Co-infections of schistosomiasis and SARS-CoV-2 appear unlikely to be critical factors in determining the severity of the disease (302), albeit it is possible. Based on an observational cohort study (303), it was shown that parasites which induce T_H2 responses resulted in a reduced risk of severe COVID-19 by dampening immune hyperactivation which is linked with pathogenesis of severe viral disease (304). When stratified by species, S. mansoni was among the parasites that implied a lower probability of severe COVID-19. Although schistosomiasis was associated with decreased SARS-CoV-2 severity, it is important to consider other helminths co-endemic in these regions, such as STHs, which may also be responsible for improving viral disease outcomes (305).

Despite the lack of information on the direct effects of COVID-19 on schistosomiasis, the pandemic has severely affected schistosomiasis transmission indirectly. With social distancing and the halting of PZQ mass drug administration, Brazil has seen a reduced amount of the population tested for schistosomiasis and, therefore, underestimated positivity rates. Furthermore, treatment of positive cases was only approximately 77% (306), inferring the potential for increased transmission of infection in the country. Moreover, in China, schistosomiasis is caused by S. japonicum and is spread by the snail vector Oncomelania hupensis. COVID-19 closures allowed this snail species to return to its natural habitat in Wuhan, increasing the risk of schistosomiasis spread (307).

Mathematical modeling has been used to determine the effects of COVID-19-caused postponement of MDA and other mitigation strategies on elimination plans for S. haematobium and S. mansoni. For both species, elimination plans have been estimated to be delayed by up to 2 years in moderate- and high-transmission areas (308). To reduce schistosomiasis infections and to attempt to achieve WHO elimination goals, these mitigation strategies need to be reinstated and maintained through future healthcare emergencies.

It is currently unclear the effects COVID-19 and schistosomiasis have on each other. Aside from the possibility of helminth-induced T_H2 responses ameliorating immune hyperactivation in severe viral disease and the contributions of the global pandemic to schistosomiasis transmission, the effects of this co-infection are controversial. SARS-CoV-2 is a relatively newly emerged pathogen, and as data are collected, these associations may become clearer. Future studies are necessary to confirm how these pathogens interact and how this interaction affects the host.

HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus causes acquired immunodeficiency syndrome and is one of the world’s most serious public health challenges. There were approximately 38.4 million people across the globe living with HIV in 2021 (309). Of these, 36.7 million were adults, and 1.7 million were children. An estimated 1.5 million individuals worldwide acquired HIV in 2021 (310), demonstrating consistent transmission. Currently, there is no cure for HIV/AIDS; however, many medications can control HIV and prevent complications (309). These medications are called antiretroviral therapy (ART). ART therapy aims to lower the amount of HIV in the blood to undetectable/untransmissible levels. HIV infection is one of the main causes of morbidity and mortality worldwide, with most of the disease concentrated in sub-Saharan Africa (311).

HIV primarily targets CD4+ T cells. Following transmission, HIV establishes itself in the mucosal tissues and spreads to the lymphoid organs within days. The virus becomes detectable in the blood around day 10 and continues to spread exponentially over the next few weeks, though in some cases, seropositivity can take up to 3 months. Most viral shedding takes place at this point (312). The immune system, with substantial contributions from CD8+ T cells, is able to achieve some control over HIV replication (313). This leads to the establishment of a “set point” where HIV replication remains relatively stable, often lasting for years (312). HIV causes a progressive loss of CD4+ T cells and a variety of immunological abnormalities through mechanisms that are likely to be multi-dimensional and are not yet fully understood (314). Pronounced immunodeficiency and development of characteristic infectious or oncologic complications occur after several years (312).

The HIV pandemic is generalized across many regions of sub-Saharan Africa, and its geographical overlap with schistosomiasis is concerning (315). In 2020, the Joint United Nations Programme on HIV/AIDS produced maps of Malawi depicting HIV incidence among young females (aged 15–24 years) at the district level for the year 2019 and of S. haematobium prevalence in the school population for the years 2012 and 2013. These maps suggest that in districts along Lake Malawi, there may be an ecological link between schistosomiasis and HIV incidence in young females (36).

Schistosomiasis appears to be a cofactor in the spread and progression of HIV/AIDS in areas where both diseases are endemic; increased emphasis on the treatment of schistosome infections in persons at risk of HIV/AIDS should be pursued (316). A further study suggests that people with chronic schistosomiasis may be more likely to become infected with HIV type-1 (HIV-1) and be impaired in viral control once infected (317). Highly active antiretroviral therapy (HAART) can effectively control viral replication in the blood but may be less effective in the gut where the majority of CD4+ T cells reside. Extensive loss of CD4+ T cells in the gut during acute HIV-1 infection suggests that, in addition to HAART, it is important to prevent viral infection of susceptible cells in the gut after initial exposure (318).

Immunological changes occurring during schistosomiasis may increase HIV transmission risk (36). It has been shown that schistosomiasis-induced pathological changes (such as inflammation and damage to the mucosal lining of genital and rectal areas) can increase the shedding of HIV and facilitate its transmission during sexual contact (316). Therefore, PZQ treatment may be beneficial in preventing HIV susceptibility (319, 320). In the northern hemisphere, men who have sex with men have been disproportionately affected by HIV-1 (321); however, it is unclear how this population compares in areas endemic for schistosomiasis. Several studies show that schistosomiasis, specifically female genital schistosomiasis among adolescents and young adults, may be associated with a higher risk of HIV acquisition (36, 320). Female genital schistosomiasis is primarily caused by S. haematobium, and less commonly by S. mansoni, and affects an estimated 20–56 million young females (322). Co-infections of HIV and female genital schistosomiasis cause mucosal changes in the intravaginal epithelium of the cervix, fornices, and vagina, as well as infertility when the upper genital tract is involved (323). In addition to Schistosoma-induced immunological changes, mast cells have been described as a reservoir of HIV-1 that can be induced by schistosome infections (324). Though it has been demonstrated that schistosomiasis may increase the risk of HIV-1, it is unclear what effect HIV-1 infection has on susceptibility to schistosomiasis (315).

Schistosomiasis may also alter immune responses to HIV. Immunoregulatory responses associated with helminth infection downregulate T_H1 immune responses associated with viral control (325). In the T_H2 cells associated with helminth infection, HIV replicates more easily (326, 327). Likewise, activated immune cells, as found around Schistosoma eggs in genital lesions or in neighboring sites, are predisposed to HIV infection (326, 328, 329). Schistosoma eggs elicit a complex cellular and humoral immune response, including upregulation of cellular CD4 and chemokine co-receptors, used by HIV-1 to enter host cells. This further increases the risk for those people with female genital schistosomiasis of being infected and transmitting HIV (49). Despite the increased risk of HIV-1 acquisition in schistosomiasis-infected individuals, a study from Mwanza, Tanzania showed that viral loads in adults were not elevated, and HIV progression was not worse in those co-infected (330, 331).

It has been found that individuals co-infected with HIV-1 and S. japonicum exhibited a lower frequency of CD4+ T cells and a higher frequency of CD8+ T cells (332). Individuals co-infected with HIV-1 and S. mansoni displayed an extra enlarged left hepatic lobe which suggests that co-infection may be associated with severe hepatosplenic disease (333). Other liver ailments have also been attributed to HIV-1 and schistosomiasis, including periportal fibrosis (334), and higher hepatotoxicity in co-infected patients on ART (335). Interestingly, in sub-Saharan Africa, it has been shown that HIV-1 infection reduced egg excretion in individuals infected with S. mansoni (315, 336, 337), suggesting that Schistosoma diagnosis by microscopy may not be ideal in co-endemic regions. The co-occurrence of HIV and schistosomiasis may be a larger hindrance to the elimination of these pathogens than initially suspected. As many populations lack accessible MDA of PZQ and ART, Schistosoma/HIV co-infections may be synergizing to increase pathology and HIV transmission to uninfected individuals.

Co-infection with HIV and schistosomiasis presents a significant public health challenge. Schistosomiasis may increase susceptibility to HIV (36, 317) and alter immune responses (36), particularly in female genital schistosomiasis (36, 320), potentially increasing HIV transmission (Fig. 5). This is especially dire in regions like sub-Saharan Africa where an estimated 30% of HIV+ individuals were not on antiretroviral treatment at the end of 2019 (338). Furthermore, the effects of HIV on schistosomiasis are noteworthy, as co-infected individuals may experience severe hepatosplenic disease (333). In adults, schistosomiasis typically precedes HIV-1 infection. In children who are born HIV+, however, HIV-1 infection precedes schistosomiasis which may present an altered immunological picture. The complex interactions between this virus and this parasite require further investigation. Additionally, their co-endemicity may hinder elimination efforts for both infectious diseases, particularly in regions with limited access to preventative measures and treatment.

Fig 5.

Proposed immunological effects of schistosomiasis and human immunodeficiency virus co-infection. Schistosomiasis exacerbates T_H2 responses, hindering T_H1 responses, including CD8+ T cells vital for viral control. Additionally, schistosomiasis [especially female genital schistosomiasis (FGS)] induces immune and pathology changes that may increase HIV susceptibility and transmission risk. Finally, schistosomiasis causes CD4+ T cell and mast cell expansion prior to HIV infection, leading to a larger HIV reservoir in the host. Post-infection, HIV contributes to a decline in CD4+ T cell counts. Co-infections of schistosomiasis and HIV may lead to increased hepatosplenic disease.

HEPATITIS VIRUSES

Hepatitis viruses are a group of viruses that primarily affect the liver, causing inflammation and damage to the organ. Acute viral hepatitis is caused by several different hepatitis viruses, including hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) (339). These viruses have different characteristics, routes of transmission, and potential health effects. HAV and HEV can be found worldwide, though they are more prevalent in areas with poor sanitation and hygiene practices. These viruses are primarily spread by fecal-oral transmission, resulting in both sporadic infections and large-scale outbreaks due to contaminated food or water (340, 341). The incidence of HBV varies by geography, with significantly higher rates in sub-Saharan Africa, parts of Asia, the Middle East, and the Amazon (342). HCV has a global distribution, affecting people in all regions of the world. Egypt, parts of central and eastern Asia, and some eastern European countries are areas of significant HCV prevalence (343). HDV is a less common hepatitis, and it requires co-infection with HBV to cause illness (344). Treatment for hepatitis viruses varies depending on the type of hepatitis and the underlying cause. With supportive care, such as rest and proper nutrition, hepatitis A and E infections are often self-limiting, and most people recover on their own within a few months. However, hepatitis B and C can lead to chronic infection and long-term liver pathology if left untreated. Treating chronic HBV and HCV aims to control the virus, reduce liver damage, and prevent complications (344). Nucleoside or nucleotide analogs such as entecavir, tenofovir, lamivudine, and adefovir are oral medications that directly target the virus and inhibit its replication. The choice of medication depends on several factors, including the severity of liver disease, viral load, and the presence of certain viral mutations (345). Regular monitoring of liver function and viral load is important to assess treatment response. Direct-acting antivirals (DAA), such as sofosbuvir, ledipasvir, velpatasvir, glecaprevir, and pibrentasvir, are now the standard of care for HCV. These medications specifically target the virus and have a high cure rate (346). DAA regimens vary depending on the specific genotype of the virus and may involve a combination of different medications taken orally for a specific duration, usually from 8 to 12 weeks (347).

Depending on the specific hepatitis virus involved, immune responses also differ. Infection with a hepatitis virus results in activation of the innate immune system as the first line of defense. Pro-inflammatory interferons contribute to the inhibition of viral replication (348, 349). NK cells and macrophages are also involved in the elimination of infected cells. CD4+ helper T cells play a critical role in coordinating the immune response, while CD8+ cytotoxic T cells directly target and kill infected cells, limiting the spread of the virus (350, 351). B cells are responsible for the production of antibodies that can neutralize the virus and prevent its entry into cells (352). In some cases, the immune response alone is not sufficient to eliminate hepatitis infections; this is particularly true for HBV and HCV. Chronic hepatitis infections can cause persistent inflammation and liver damage (348, 353).

Schistosomiasis and hepatitis co-infection is reported in many countries, notably in Egypt (354). Here, the prevalence of schistosomiasis in patients with HCV infection was reported to be between 27.3% and 50% across two studies (355, 356). Furthermore, a high prevalence of HCV and S. mansoni co-infection was reported among workers employed in sewage treatment plants (354). Co-infection of HBV and S. mansoni ranged from 19.6% to 33.0% (357). It is interesting to note that a high prevalence was also demonstrated in China, where about 58.4% of the patients with chronic S. japonicum had HBV (354) and in Hubei, specifically, where the prevalence of HBV in schistosomiasis patients was much higher (25.37%) compared to those without schistosomiasis (0.62%) (358). The risk of becoming infected with HBV was significantly higher in patients with HCV and schistosomiasis compared to those without schistosomiasis. Similarly, in Egypt, the prevalence of HBV was higher in patients already co-infected with HCV and schistosomiasis (12.8%) than in those without schistosomiasis (8.5%) (356). Moreover, chronic schistosomiasis patients have had a higher risk of HCV/HBV co-infection due to parenteral schistosomiasis treatment using non-sterile syringes, blood transfusion for anemia, surgery, and endoscopy (359, 360).

One review has examined the pathology of Schistosoma and HBV/HCV co-infections between 1975 and the end of 2014 (361). The authors found that the clinical course of illness once an individual was co-infected with Schistosoma and either HBV or HCV was typically more severe than those which were mono-infected. For both viruses, co-infection resulted in detrimental pathologies leading to higher mortality. Other reviews have also demonstrated the importance of hepatitis-schistosomiasis co-infections (357, 362, 363). One postulated that vaccination may be a solution to co-endemicity (364), though a recent preprint demonstrated that Schistosoma infection blunts HBV-vaccine responses, highlighting that it may be necessary to clear the helminth infection pre-vaccination (365).

The effects of schistosomes on HBV and HCV have been thoroughly examined by Bullington et al. (366). In patients with hepatosplenic schistosomiasis, HBV and HCV co-infections have been shown to be associated with a marked depression of cell-mediated immune responses (364).

In cases of HCV, some studies reported impairment of HCV-specific CD4+ T cell responses. Co-infections of hepatitis C and schistosomiasis also resulted in a promotion of T_H2 responses (IL-4, IL-10) over T_H1 responses, which may explain the synergistic relationship of Schistosoma-HCV on both liver fibrosis and mortality (354). In co-infected patients, increased HCV RNA titers, histologic activity, and incidence of cirrhosis/hepatocellular carcinoma were observed (367), in addition to liver and spleen stiffness (368).

Although the effects of Schistosoma on HBV infection remain a subject of debate as schistosome-induced factors like IFNγ and NO can inhibit HBV replication (369) and one study did not find a clear association between schistosomiasis and worsening of HBV infection (370), most reviews conclude that HBV and schistosomiasis co-infections also led to poorer prognoses (354, 361). Chronic schistosomiasis and HBV co-infection may progress from advanced cirrhosis to hepatocellular carcinoma, with co-infection found to exaggerate liver function abnormalities, histological changes, and fibrosis more than HBV mono-infection (371–373). This was supported by a study which reported that HBV in association with hepatosplenic schistosomiasis led to worse outcomes (358).

In conclusion, hepatitis viruses, with their various types and routes of transmission, present distinct challenges in terms of diagnosis, treatment, and the immune responses they elicit. Co-infection with schistosomiasis further complicates clinical course and outcomes, often resulting in more severe liver pathologies and increased mortality (354, 361). As we navigate this complicated landscape, primary prevention of HCV and HBV infections remains crucial, especially in regions where schistosomiasis is endemic. There is a pressing need for continued research to fully understand the dynamics of these co-infections. This research should encompass various aspects, including the potential influence of co-infections on mass HBV vaccination, which will aid in developing more effective strategies for managing and preventing these infections.

OTHER PATHOGENS AND MULTIPLE CO-INFECTIONS

Cytomegalovirus (CMV) is a common virus belonging to the herpesvirus family (374). CMV is common worldwide infecting a substantial number of individuals at some point in their lives, though its prevalence varies in different population groups and geographical regions (375). CMV seroprevalence is generally higher in women, older age groups, lower socioeconomic status, and low- to middle-income countries (376). Among women of reproductive age, global CMV seroprevalence ranges from 45% to 100% (376). CMV can be found in various bodily fluids, including saliva, urine, blood, semen, and breast milk. Common routes of transmission include sexual contact, organ transplantation, blood transfusion, and vertical transmission during pregnancy (377). Vertical transmission involves CMV passing from a pregnant person to their fetus, resulting in congenital CMV infection (378). Congenital CMV infection can cause a range of health problems including hearing loss, developmental delay, and neurological abnormalities (379).

CMV is of particular concern for people with weakened immune systems, such as those with HIV/AIDS, organ transplant recipients, or those undergoing chemotherapy. The immune response to cytomegalovirus is complex and involves several different components of the immune system (380–382). NK cells play a crucial role in recognizing and eliminating CMV-infected cells (383).

Since NK cells are important for CMV elimination and hepatic NK cell function is inhibited via the T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain receptor in schistosomiasis-induced liver fibrosis, co-infections of CMV and schistosomiasis may potentiate viral load (384, 385). Also, it is worth noting that individuals with weakened immune systems, such as those with advanced schistosomiasis or other chronic illnesses, may be more susceptible to CMV infection and its associated complications which highlights the importance of accurate diagnosis and the appropriate management of these conditions.

Differently, arboviruses, or arthropod-transmitted viruses, are a group of viruses that are transmitted to humans and other animals primarily through the bites of infected arthropod vectors such as mosquitoes, ticks, and sandflies (386). Arboviruses are found in different parts of the world, and their distribution is influenced by the presence of suitable vectors and reservoir hosts (387). The presence and abundance of arthropod vectors strongly influence the transmission dynamics of arboviruses (388). Factors such as vector species, their distribution, behavior, and vector competence contribute to the epidemiology of arboviral diseases (388). Some arboviruses have reservoir hosts, typically mammals, which maintain the virus in nature and can serve as sources for transmission to vectors (389). Infected individuals or vectors can carry the virus to regions where it is not endemic, potentially leading to localized outbreaks or establishing new transmission cycles (390). Climate factors, including temperature, precipitation patterns, and habitat changes, can influence the distribution and abundance of arthropod vectors and alter the epidemiology of arboviral diseases (391). Climate change may even expand or shift the geographic range of certain vectors and increase the risk of arboviral transmission in previously unaffected areas (392). Notably, arboviruses include a diverse group of viruses, such as dengue, Zika, chikungunya, yellow fever, and others, each of which has different characteristics and interactions with the host’s immune system (393).

There is limited research specifically on the association between schistosomiasis and arboviruses; schistosomiasis primarily affects human blood vessels and can lead to chronic inflammation, immune modulation, and alterations in the immune response (394), and the susceptibility and severity of arboviral infections may be influenced by this altered immune environment (395). Some studies suggest that co-infection or previous exposure to schistosomiasis may be a modulator of the immune response to arboviral infections (396), which can have an impact on the clinical outcome or severity of the disease (397). Despite the lack of research on these co-infections, these pathogens are often co-endemic; for example, in Brazil, where a young person infected with Zika virus exhibited testicular inflammation and extensive loss of testicular structure, with granulomas induced by S. mansoni eggs (398). In areas where schistosomiasis and arboviruses co-occur, it is important to address both infections through a comprehensive set of public health interventions.

Although extensive, this review is not exhaustive. Schistosoma spp. are prevalent in 78 countries worldwide, resulting in chronic infections, making schistosomiasis a common co-infecting pathogen. Some examples of other Schistosoma co-infecting pathogens which were not discussed in this review include Helicobacter pylori (399), human papilloma virus (51), and human T lymphocyte virus-1 (400) to name a few. Moreover, it is important to note that this review did not address potential co-occurrence of fungal infections alongside schistosomiasis.

Adding more depth and convolution to Schistosoma co-infections are individuals infected with three (or more) pathogens. One example recently published is of a Polish traveler who returned from the Democratic Republic of Congo, presenting with disseminated skin rash and eosinophilia, and was diagnosed with Schistosoma sp., Strongyloides stercoralis, Trichuris trichuria, and Blastocystis sp. (401). Another example is a Ghanaian immigrant who was seropositive for Schistosoma sp., filaria, and Strongyloides sp. (402). Some epidemiologic studies have been completed in cohorts of people with Schistosoma co-infections with two other pathogens. Cases of anemia have been seen in Ethiopian children infected with Schistosoma mansoni, Plasmodium sp., and hookworm (100). Schistosoma mansoni was also reported to increase the risk of TB disease in HIV+ Kenyan adults (403), while it did not contribute to mortality or recurrence of non-typhoidal Salmonella bacteremia in HIV+ Malawian adults (404).

Given the infinite potential for co-infections involving Schistosoma sp., it is unfeasible to comprehensively address all of them within a single review. However, it is evident that helminthic parasites, by modulating the immune system, play a significant role in influencing other infections and diseases.

CONCLUSIONS

Despite their prevalence, limited work has been published on the co-infections of Schistosoma spp. and other pathogens. Unfortunately, this comes with the territory of many neglected tropical diseases. Yet, the urgent need to obtain insight into the epidemiology, pathogenesis, and driving immune mechanisms of Schistosoma co-infections can be supported by the sheer number of individuals at risk of disease (8). Figure 6 depicts a summarized view of the prevalence of co-infecting pathogens with Schistosoma spp. As this map is broadly representative and cannot display whole special regions, we can appreciate the underestimation of co-endemicity between pathogens.

Fig 6.

Schistosoma and co-infections world map. The navy-blue shading on the map indicates regions where Schistosoma spp. are endemic. Within these areas, colored dots mark co-endemic regions for other pathogens. Geographical regions are categorized as South America, Africa, the Middle East, India, China, and the Southeast Asian nations. Intestinal protozoa were omitted as they are ubiquitous. Salmonella, SARS-CoV-2, and cytomegalovirus are also ubiquitous and have been marked in areas where they are most prevalent.

Being a chronic infection, which has evolved with humans (405), schistosomes carefully balance parasite survival with host pathology (406). This is exemplified through the theory of concomitant immunity where adult schistosomes protect the host from incoming larval stages of the same species for their own benefit (407). How this balance is affected when other pathogens are present is poorly understood.

Through the literature we found that Schistosoma spp., when co-infecting with other schistosomes, led to higher infection intensities, ectopic egg elimination (23, 53, 58, 59, 61, 64), and an increased risk of species hybridization which could enhance transmission (64, 71–76). Outcomes of Schistosoma and STH co-infections are more complex, as both worsened and improved outcomes have been shown (7, 34). While parasite burden was unchanged in some cases, in others, liver pathology and egg granuloma sizes were both increased (7, 86–89).

With most protozoan parasites, which require T_H1 immune responses for protection, schistosomiasis-induced T_H2 immune responses often led to worse prognoses. Cutaneous leishmaniasis required longer healing times post-treatment, and higher parasite burdens were observed in co-infected mice (134). Co-infection with trypanosomes generated increased levels of Trypanosoma parasitemia and Schistosoma egg-induced granulomas (144, 145). Toxoplasma gondii reduced helminth T_H2 responses resulting in increased liver pathology and animal mortality (171). Finally, Entamoeba and Schistosoma co-infections yielded worsened parasite burdens of E. histolytica and animal morbidity (7, 190).

All the bacterial co-infections reviewed in this paper demonstrated that when present with schistosomiasis, outcomes were worse. Schistosomiasis is acknowledged to push latent Mycobacterium tuberculosis to reactivation (37) and may increase the transmission of Mycobacterium leprae (219–221). While schistosomiasis parasite burden is lower during Salmonella co-infection, the risk of renal complications is increased (237, 242, 243) and antibiotic efficacy is reduced until anthelmintics are administered (235, 239, 246). Schistosomiasis, particularly S. haematobium, has also been seen to increase the risk of urinary tract infections by several bacterial species (259, 262, 264, 265, 271–277).

Most viruses discussed here also led to worse outcomes when co-infecting with schistosomiasis. Schistosomiasis reduced protective T_H1 immunity from HIV (325), resulting in increased HIV risk and transmission (36, 317), which is of great significance in cases of female genital schistosomiasis (323). Hepatitis viruses and schistosomiasis generally led to severe liver pathology and mortality (354, 361). Although research is limited, schistosomiasis may also impact the progression of CMV and arboviruses which are common in schistosomiasis endemic regions.

Intriguingly, when co-infecting with schistosomiasis, only one parasite and one viral pathogen created a positive outcome for the host, being malaria and SARS-CoV-2, respectively. In cases of Plasmodium and Schistosoma co-infection, despite an increased presentation of anemia and hematuria (100–103, 105, 106), malaria parasite burden was reduced resulting in better outcomes. In the case of SARS-CoV-2, regression modeling of an observational cohort study implied that T_H2-inducing parasites, including Schistosoma, decreased the risk of severe viral disease caused by immune hyperactivation, albeit this has yet to be confirmed in epidemiological data.

Despite the contentious data from Schistosoma and STH co-infections, and the amelioration of disease in Schistosoma co-infections with Plasmodium and possibly SARS-CoV-2, co-infections with schistosomiasis generally led to worsened outcomes as outlined in Table 1.

TABLE 1.

Schistosoma spp. and co-infection summary table

Co-infection with Schistosoma spp.	Immunological outcomes	Pathological outcomes	Pathogen outcomes
Schistosoma	Increased TH2 responses (56)	Decreased liver pathology (23) Increased bladder pathology (63)	Ectopic egg elimination (23, 53, 58, 59, 61) Increased parasite burdens (23, 53, 55, 61, 68)
Soil-transmitted helminths	Increased TH2 and TREG responses (84) and serum IgE (85)	Pathology changes dependent on co-infecting STH	Varying infection burdens depending on various factors
Plasmodium	Increased anti-malaria IgG, IL-4 (109–111), and TREG cells (114)	Increased risk of anemia (100–103, 105, 106)	Decreased Plasmodium burden (102, 104, 115)
Leishmania	Increased TH2 responses: IgE, IL-4, IL-5 (129) Decreased TH1 responses in lymph nodes: IFNγ, NO, TNFα (mice) (134)	Smaller CL lesions (humans) (129) and larger lesions (mice) (134) which took longer to heal	Increased levels of L. donovani amastigotes (mice) (135)
Trypanosoma	Increased IL-10 (145) Reduced IFNγ (145)	Splenomegaly (144) Increased number of liver granulomas, with higher cellularity and less fibrosis (145) Higher mortality (144)	Increased Trypanosoma parasitemia (144, 145) Decreased Schistosoma burden (7)
Toxoplasma	Increased serum IgE and TNFα (169, 170) Suppressed protective TH2 responses in livers (171)	Increased mortality when Toxoplasma followed Schistosoma infection (169, 170) Decreased Toxoplasma intestinal pathology (171) Coagulative necrosis with extensive hepatocyte vacuolization in livers (171)
Entamoeba		Higher morbidity (7)	Higher Entamoeba burdens (7)
Mycobacteria	Increased TH2 responses, type 2 granulomas, IL-4204, TREG cells (206) Dampened γδ T cell immune responses (218) Reduction of TH1 CD4+ T cells (208)	Increased risk of clinical TB (196), TB reactivation (196, 197), and disseminated infection (196) Increased risk of leprosy transmission (M. leprae) (219–221)
Salmonella	Increased anti-fibrotic TH1 responses in the liver, IL-10 (249), IFNγ (253) Decreased type 2 mediators: IL-4 (249, 253), IL-5 (249)	Prolonged fever and hepatosplenomegaly (235) Increased mortality (hamsters) (252), renal pathology (237, 242, 243), and liver pathology; egg granulomas were congested and necrotic (249)	Decreased effectiveness of antibiotic treatment (246) Enhanced Salmonella colonization (235, 247–249) Lowered Schistosoma worm and egg burden (249, 253)
Urinary tract infection-causing agents	Increased IL-4 (385) Reduced invariant NK T cell-mediated killing (286) and antimicrobial peptides in the bladder (287)	Increased risk of UTI acquisition (259, 262, 264, 265, 270–277)
Severe acute respiratory syndrome coronavirus 2	Dampened immune hyperactivation (303)	Potential reduced risk of severe disease (303)
Human immunodeficiency virus	Increased TH2 responses (326, 327) Decreased TH1 responses and protective CD8+ cells (325)	Increased HIV risk and transmission (36, 317) Female genital schistosomiasis and HIV can lead to genital pathologies and infertility (323) May lead to liver ailments (333): periportal fibrosis (334) and higher hepatotoxicity (335)	Potential for reduced egg excretion in feces (315, 336, 337) HIV progression was not worse in co-infected (330, 331)
Hepatitis B virus and hepatitis C virus	Increased TH2 responses: IL-4, IL-10 (354) Decreased cell-mediated immune responses (364)	Clinical course of illness becomes more severe (HBV and HCV) (354, 361): liver fibrosis and mortality (372, 373), incidence of cirrhosis/hepatocellular carcinoma (367, 371)	Increased HCV RNA titers (367)

Ultimately, co-infections with schistosomiasis are underreported, understudied, and undertreated to an even greater extent than mono-infections with neglected tropical diseases. Yet these co-infections involve complex interactions of immunological factors and changes in pathology, often resulting in exacerbated disease. Research into Schistosoma co-infections, as demonstrated in this review, is beginning to describe these interactions. However, comprehensive epidemiological data are lacking, highlighting the need for larger cohort studies to determine the immunology of co-infecting pathogens. It is essential for the scientific research community to prioritize and expand this research further to better understand transmission kinetics, treatment, and vaccination challenges associated with co-infections. Acknowledging the reality of co-infections, and their immunological and pathological effects on each other, is crucial to improving patient care and developing effective intervention strategies in the coming years.

Biographies

Dilhan Perera is completing his PhD in the division of Experimental Medicine, McGill University (Montreal, QC, Canada). Under the supervision of Dr. Momar Ndao, Dilhan’s current research focus is vaccine development and immunology for schistosomiasis and COVID-19. Dilhan earned his undergraduate degree in Microbiology and Immunology at McGill, and has spent time as a research assistant at the Mayo Clinic (Rochester, MN, USA) and KGK Science (London, ON, Canada) conducting in silico analyses of aneurysms and assisting with nutraceutical clinical trials, respectively. Since 2017, he has published eleven peer-reviewed manuscripts, both reviews and primary research, and serves as the secretary for the Food and Environmental Parasitology Network (Health Canada). Dilhan currently holds a Canadian Institutes of Health Research Doctoral Award, and has been awarded with several institutional presentation awards and awards dedicated to teaching, mentorship, and enhancing student learning.

Cal Koger-Pease is completing their PhD in the division of Experimental Medicine, McGill University (Montreal, QC, Canada). Under the supervision of Dr. Momar Ndao, Cal’s current research focus is developing viral vectored vaccines and elucidating correlates of protection for schistosomiasis. Cal earned their undergraduate degree in Microbiology and Immunology at McGill, where they completed an undergraduate honours thesis focusing on short interfering RNA treatments for COVID-19. Since 2023, they have published two peer-reviewed manuscripts.

Kayla Paulini is completing her PhD in the department of Microbiology and Immunology at McGill University (Montreal, QC, Canada). Under the supervision of Dr. Greg Matlashewski, Kayla studies various phosphatases in Leishmania and how they pertain to infection. She earned her bachelor’s degree in Microbiology and Immunology at McGill University in 2017 after gaining research experience in three different labs working with Caulobacter crescentus, Pseudomonas aeruginosa, and Heligmosomoides bakeri. After her bachelor’s degree, Kayla worked as a lab technician in the food microbiology industry before returning to graduate school. Currently, Kayla holds a Fond de Recherche du Québec en Santé doctoral award.

Mohamed Daoudi is a post-doctoral fellow in the Ndao lab in the department of Microbiology and Immunology at McGill University (Montreal, QC, Canada). He holds a PhD in Microbiology and Medical Entomology focusing on investigating geographical distribution and vectorial capacity of the Moroccan population of sand flies. His current research project focuses on the utilisation of extracellular vesicles to develop advanced methods for the early detection of infections, the creation of precise diagnostic tools, and the preventive measures against Tick-borne diseases and schistosomiasis. Mohamed has published nine peer-reviewed manuscripts since 2019, received the Federation of African Immunological Societies Award in 2019, and received a grant from the Italian Ministry of Foreign Affairs and International Cooperation in 2020.

Momar Ndao is a Doctor of Veterinary Medicine, and earned his MSc and PhD in Tropical Medicine in International Health and Tropical Diseases at the Institute of Tropical Medicine (Antwerp, Belgium). He is currently an Associate Professor at McGill University in the Faculty of Medicine (Montreal, QC, Canada) and his research focuses on parasite vaccinology, diagnostics, and biomarker discovery using proteomic analyses. Dr. Ndao serves as the Director of the Canadian National Reference Centre for Parasitology (NRCP) and holds the following appointments: Chair of the Facility Animal Care Committee (FACC) Research Institute of the McGill University Health Centre Glen, Co-chair of the Food and Environmental Parasitology Network (Health Canada), among others. He is also a member of several boards and committees including: the World Federation of Parasitologists, the executive board of the International Federation of Tropical Medicine, and the Scientific Committee of Pasteur Institute, to name a few.