Overview of the host immune response to P. falciparum malaria

Abstract

The host immune response to malaria is a complex interplay between the parasite, Plasmodium, and the human immune system. Upon infection, various components of the immune system, including innate and adaptive responses, are mobilized to combat the parasite. Innate immunity provides the initial defense, with cells such as macrophages, dendritic cells, and natural killer cells recognizing and responding to the parasite. Additionally, inflammatory cytokines are released to coordinate the immune response. The adaptive immune response, primarily involving T and B lymphocytes, plays a crucial role in controlling and eliminating the parasite. T cells recognize and destroy infected cells, while B cells produce antibodies that target specific antigens on the parasite's surface. These antibodies can neutralize the parasite, block its invasion of host cells, and facilitate its clearance by phagocytes. However, the development of protective immunity against malaria is complex and influenced by various factors, including parasite diversity, host genetics, and prior exposure to the parasite. While some individuals develop partial immunity over time, others remain susceptible to severe disease. Understanding the intricacies of the host immune response to malaria is essential for the development of effective vaccines and therapies to combat this global health burden.

Introduction

Malaria is predominantly transmitted by the bite of infected Anopheles mosquitoes (WHO 2019). The disease is most prevalent in tropical and subtropical regions, particularly in sub-Saharan Africa, which accounts for the majority of global cases and deaths (WHO 2019). Malaria also affects parts of South Asia, Southeast Asia, Latin America, and Oceania. The epidemiology of malaria is influenced by factors such as climate, mosquito vector behavior, human immunity, and socio-economic conditions (WHO 2019; Dosoo et al. 2020). Effective malaria control strategies include the use of insecticide-treated bed nets, indoor residual spraying, prompt diagnosis, and treatment with antimalarial drugs, and ongoing research into vaccines. Despite significant progress in reducing the incidence and mortality of malaria in recent years, the disease remains a major public health challenge, particularly in resource-limited settings (Dosoo et al. 2020).

It takes years for the human body to build up natural protection against malaria, even in places where the disease is common, and people are regularly exposed to the parasite (Day and Marsh 1991). This immunity is specific to the particular type of parasite causing malaria, meaning the body's immune system responds to and fights off specific strains of the P. falciparum parasite (Day and Marsh 1991). However, this immunity only applies to certain stages of the parasite's life cycle, such as the erythrocytic stage, and doesn't provide protection against other stages like the sporozoite or intrahepatic stages (Plebanski and Hill 2000; Vermeulen et al. 1985). Additionally, factors like age, genetics, pregnancy, nutritional health, and other infections influence the effectiveness of antimalarial immunity. Children under five years old living in areas where malaria is prevalent are particularly vulnerable. Despite the immune response that develops over time, subsequent infections can still occur due to the complex life cycle of the Plasmodium parasite, which involves multiple organs and can easily evade the host's immune defenses (Fig. 1) (Winzeler 2008).

Fig. 1.

The life cycle of the P. falciparum in the human and the mosquito

During the erythrocytic stages, the malaria parasite resides within red blood cells (RBCs), which means it can travel to different organs as the RBCs move throughout the body. Consequently, immune responses targeted at infected RBCs can potentially impact multiple organs. Understanding how the host's immune system reacts to P. falciparum parasites and how the parasite evades immunity at various stages of its life cycle is crucial for vaccine development and treating those affected by the disease (Good et al. 2005). Despite Plasmodium's long history spanning over 5000 years, its intricate life cycle elicits a complex response from the host's immune system, involving diverse cell types, malaria-specific antibodies, and various cytokines. These components of the immune response operate in a coordinated manner throughout different stages of the parasite's life cycle (Good and Doolan 1999).

Immune mechanisms against the pre-hepatic P. falciparum infection stage

The significance of antibodies in controlling sporozoites was initially demonstrated in rodent malaria studies, where immunization with weakened Plasmodium berghei sporozoites prompted the production of neutralizing antibodies against them (Nussenzweig et al. 1967). This finding has been replicated in humans, confirming the production of sporozoite-specific antibodies even in naturally occurring infections in malaria-endemic regions (Rieckmann et al. 1979; Hoffman et al. 1986). While research has shown that antigen-specific monoclonal antibodies can prevent P. falciparum sporozoites from invading hepatocytes in laboratory settings, effectively halting their development within these liver cells, relying solely on antibodies isn't a complete solution (Hoffman et al. 1986).

This limitation arises because sporozoites typically invade hepatocytes within a very short timeframe, ranging from 2 to 30 minutes after inoculation. For antibody-mediated protection to be effective, these antibodies must be present in the bloodstream at high concentrations and act quickly upon infection to prevent hepatocyte invasion (Good and Doolan 1999). Due to this narrow window of opportunity, protective immunity solely mediated by antibodies against the sporozoite stage isn't always successful, even if antibodies are eventually produced in large quantities. Sporozoites that evade antibody neutralization can quickly infect host liver cells during the pre-erythrocytic stage (Plebanski and Hill 2000).

In individuals from highly malaria-endemic regions, antibodies in their blood serum target three crucial antigens during this stage of the parasite's life cycle (Druilhe et al. 1986). These antigens include Thrombospondin-related adhesive protein (TRAP), Circumsporozoite protein (CSP), both of which have been identified as potential vaccine candidates, and Liver Stage Antigen 1 (LSA1) (Kisalu et al. 2018). The antibody responses against CSP, TRAP, and LSA1 play a pivotal role in inhibiting sporozoite invasion of liver cells, offering protection against infection, and decreasing the likelihood of developing clinical malaria (Biswas et al. 2014; Lu et al. 2020). The most advanced malaria vaccine to date, RTS,S, contains the CSP antigen and has been approved and is being implemented in pilot programs whilst R21 is still in the clinical trial phase but showing promising results that could lead to approval in the near future (John et al. 2005). These vaccine triggers the production of antibodies that can prevent sporozoite invasion of liver cells and also stimulates a cellular response that helps in eliminating infected liver cells (Biswas et al. 2014). The RTS,S vaccine has been rolled out in three African countries but is < 50% protective, suggesting further iterations are required (John et al. 2008; El-Moamly and El-Sweify 2023).

There are other candidates in the pipeline that show promise for incorporation into second-generation vaccines. One leading candidate antigen is P. falciparum Reticulocyte Binding homologue 5 (Rh5, PF3D7_0424100), which is currently advancing through clinical trials (Adepoju 2019). Rh5 is the smallest in the Reticulocyte Binding Protein homolog (Rh) family that includes Rh1, Rh2a, Rh2b and Rh4 (RTS,S Clinical Trials Partnership 2015; Payne et al. 2017). Furthermore, it is the only member of the Rh family without a transmembrane domain. Rh5 has been shown to be refractory to gene knockout experiments, suggesting it plays an essential role in the invasion of erythrocytes via interactions with the erythrocyte receptor basigin (BSG) (RTS,S Clinical Trials Partnership 2015; Payne et al. 2017; Hayton et al. 2008). Both monoclonal and polyclonal anti-Rh5 antibodies inhibit erythrocyte invasion of multiple parasite strains by blocking the Rh5-BSG interaction in vitro (Baum et al. 2009; Crosnier et al. 2011; Douglas et al. 2011, 2014; Bustamante et al. 2013).

Studies on antibodies targeting sporozoite antigens suggest that the magnitude of the antibody response is influenced by age and the dose of exposure (Alanine et al. 2019). While this response correlates with partial protection in certain areas, it doesn't provide complete immunity against malaria (Douglas et al. 2015). However, a new malaria vaccine, R21/Matrix-M, showed over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. It was also seen during the study that, R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. (Feng et al. 2022)

Immune mechanisms against the pre-erythrocytic P. falciparum infection stage

Protective immunity against the pre-erythrocytic stage targets P. falciparum as it develops within hepatocytes (Doolan et al. 2009). This immunity primarily relies on CD8+ and CD4+ T cells, which recognize parasite-derived peptides presented respectively by MHC class I and class II molecules on infected hepatocytes (Datoo et al. 2024). Studies in mice models have shown that CD8+ T cells play a crucial role in mediating protection against the pre-erythrocytic stage. Depletion of CD8+ T cells in vivo abolishes this protection, while adoptive transfer of CD8+ T cells to naïve mice confers protection, highlighting their pivotal role in immunity (Holz et al. 2016).

Protection against malaria at the pre-erythrocytic stage involves CD8+ cytotoxic T lymphocytes (CTLs) along with cytokines and factors like nitric oxide (Holz et al. 2016). Interferon gamma (IFN-γ) treatment of P. falciparum-infected hepatocytes in vitro can eradicate the parasite from culture. IFN-γ is also associated with stimulating nitric oxide production both in vitro and in vivo following P. falciparum sporozoite infection (Kurup et al. 2019). However, natural exposure to parasite antigens may not sufficiently trigger robust T-cell responses against the pre-erythrocytic stages due to the low antigen dose, estimated at 10–100 sporozoites per mosquito bite. This dose may not effectively elicit a strong immune response, as seen in studies. Notably, achieving a high degree of sterile protection requires intravenous injection of several hundred thousand sporozoites (Tsuji and Zavala 2003).

Immune mechanisms against the erythrocytic P. falciparum infection stage

Parasites thrive within red blood cells (RBCs), which lack MHC molecules. However, infected RBCs (iRBCs) display parasite-encoded variant surface antigens (VSAs), with P. falciparum erythrocyte membrane protein (PfEMP1) being the most extensively studied antigen (Vermeulen et al. 1985; Winzeler 2008; Good et al. 2005). Each parasite harbors around 60 variant gene copies for PfEMP1, generating a vast repertoire of PfEMP1 sequences. These variants facilitate binding to diverse host tissues through various host receptors and domains (Hafalla et al. 2006; Seder et al. 2013; Tembo et al. 2014). Other newly discovered malaria antigens such as p. falciparum erythrocyte membrane and merozoite antigen 1 (PfEMMA1), P. falciparum Reticulocyte Binding homologue 5 (Rh5) and glutamic acid-rich protein (GARP) have been noted to play similar role (Kessler et al. 2017; Craig et al. 2003; Michelow et al. 2021). Clearance of a parasite clone typically corresponds with the emergence of a VSA-specific antibody response targeting that particular clone. Meanwhile, other parasites may switch expression to different VSAs, enabling their survival and proliferation. Moreover, the new clone may exhibit altered tissue adhesion properties, influencing disease pathology (Ndwiga et al. 2021). Both intra- and inter-clonal characteristics of VSAs hold potential implications for the development of vaccines targeting the erythrocytic stage.

The products released from ruptured infected red blood cells (iRBCs) consist of a complex mixture of glycoproteins and glycolipids with endotoxin-like properties, primarily composed of glycosylphosphatidyinositols (GPI) (Hon and Matuschewski 2020). These compounds can directly stimulate the production of tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) through an innate pathway involving natural killer (NK) cells, macrophages, and gamma/delta (γδ) T cells. Concurrently, antigen-specific alpha/beta (αβ) T cells are activated (Marsh and Kinyanjui 2006; Mandala et al. 2021). The relatively low levels of IFN-γ and TNF-α produced during this stage are associated with inhibiting parasite replication, thereby reducing parasitemia levels and providing an additional layer of malaria disease prevention (Marsh and Kinyanjui 2006; Mandala et al. 2021).

A decrease in the proportion of non-classical monocytes in the periphery has been associated with fatal cerebral malaria cases, indicating a potential role for this monocyte subset in malaria resolution (Riley 1999). However, it is important to note that while the recruitment of activated monocytes and macrophages to the infection site is crucial for malaria clearance, these cell types have also been linked to adverse clinical outcomes, particularly in cerebral malaria cases, due to their tendency to migrate to and sequester in cerebral microvasculature (Royo et al. 2019). The spleen is a critical immunological site during the blood stage of malaria infection, playing a key role in the clearance of parasitized red blood cells (pRBCs) and the regulation of immune responses (Ozarslan et al. 2019). As a highly vascularized organ, the spleen filters blood and is strategically positioned to detect and respond to blood-borne pathogens, including Plasmodium-infected erythrocytes (Ghosh and Stumhofer 2021).

The spleen acts as a blood filter, trapping and removing pRBCs through its unique architecture, which includes the red pulp and the marginal zone (Ozarslan et al. 2019; Ghosh and Stumhofer 2021). The mechanical filtration system ensures that pRBCs are retained within the spleen for further processing (Ozarslan et al. 2019; Ghosh and Stumhofer 2021). Furthermore, the spleen act as a hub for immune cell interactions by housing a variety of immune cells, including macrophages, dendritic cells, B cells, and T cells, which are crucial for initiating and sustaining immune responses against the malaria parasite (Portillo et al. 2012). The splenic macrophages, particularly those located in the red pulp, are specialized in phagocytosing pRBCs (Gomes et al. 2016). These macrophages recognize and engulf pRBCs that display altered surface properties due to parasite infection (Gomes et al. 2016). The macrophages' phagocytic activity is enhanced by opsonizing antibodies and complement proteins that tag the pRBCs for destruction (Gomes et al. 2016). After engulfing pRBCs, splenic macrophages process and present Plasmodium antigens on their surface to T cells. This antigen presentation is critical for the activation of both CD4+ helper T cells and CD8+ cytotoxic T cells, leading to a robust adaptive immune response (Gomes et al. 2016; Nagelkerke et al. 2018). Again, splenic macrophages produce a variety of cytokines and chemokines in response to malaria infection (Alberts et al. 2002a). These signaling molecules help recruit and activate other immune cells, enhancing the overall immune response. For example, cytokines such as IFN-γ can activate other macrophages and enhance their microbicidal activities (Alberts et al. 2002a). Finally, splenic macrophages also play a role in the maintenance of memory B cells and the rapid production of antibodies upon re-exposure to the malaria parasite, contributing to long-term immunity (Dunst et al. 2017).

The immune response to malaria involves a complex interplay of antibodies, B cells, and T cells, including Th1 and Tfh cells, each playing a crucial role in protection against the parasite (Pérez-Mazliah et al. 2020). Antibodies are central to the immune defense against malaria (Calle et al. 2021). They target the different stages of the Plasmodium parasite, from sporozoites to merozoites and gametocytes. By neutralizing sporozoites, antibodies prevent the parasite from invading liver cells (Calle et al. 2021). During the blood stage, antibodies opsonize merozoites, facilitating their destruction by phagocytes and inhibiting their ability to invade red blood cells (Long and Zavala 2017). Antibodies can also block the transmission of gametocytes to mosquitoes, interrupting the parasite's lifecycle (Lelliott et al. 2015). Upon encountering malaria antigens, B cells differentiate into plasma cells, which secrete specific antibodies against the parasite (Kwapong et al. 2023). Memory B cells are also generated, providing long-term immunity and a quicker response upon subsequent exposures to the parasite (Silveira et al. 2018).

T cells, particularly CD4+ helper T cells, are essential in coordinating the immune response (Portugal et al. 2015). They assist in the activation of B cells and the production of antibodies, as well as the activation of other immune cells (Portugal et al. 2015). Th1 cells produce cytokines such as IFN-γ, which activate macrophages and enhance their ability to kill intracellular parasites. They also help in promoting the cellular immune response, which is crucial for controlling liver-stage parasites (Luckheeram et al. 2012). Furthermore, T follicular helper (Tfh) cells are vital for the formation and maintenance of germinal centers in lymphoid tissues (Siddiqui et al. 2020). They provide critical help to B cells, promoting their differentiation into high-affinity antibody-producing plasma cells and memory B cells. Tfh cells are essential for a robust and sustained antibody response against malaria (Crotty 2014). It is worthy to note that, the immune protection against malaria involves a coordinated effort of antibodies that neutralize and destroy the parasite, B cells that produce these antibodies and form memory responses, and T cells that orchestrate and enhance these processes through their cytokine production and direct cellular interactions. This multi-faceted immune response is essential for effective defense and long-term immunity against malaria (Portugal et al. 2015; Luckheeram et al. 2012; Siddiqui et al. 2020; Crotty 2014).

Immune mechanisms against the gametocyte stage of P. falciparum infection

The immune responses against the malaria parasites, particularly during the gametocyte stage, are crucial for both protection and reduction in transmission (Soon et al. 2021). As previously mentioned, during the early stages of asexual parasites infecting red blood cells (aiRBCs), these cells are present in circulation (Vermeulen et al. 1985; Winzeler 2008; Good et al. 2005). As the parasite matures within the RBC, it secretes numerous proteins into the host cell, altering its physical and immunogenic characteristics (Kengne-Ouafo et al. 2019). A subset of asexual blood-stage parasites transforms into the sexual, mosquito-transmissible form within RBCs (Kengne-Ouafo et al. 2019). Within these gametocyte-infected RBCs (giRBCs), the parasite progresses through five distinct morphological stages (stage I-V). Similar to mature aiRBCs, immature giRBCs (stage I-III) display parasite proteins on the host cell surface and localize to various sites in the host, primarily the bone marrow and spleen (Maier et al. 2009).

Upon reaching maturity, gametocytes re-enter circulation, where they can be ingested by female Anopheles mosquitoes during a blood meal and undergo further development. However, while in peripheral circulation, the human host mounts an immune response against the gametocytes (Dantzler et al. 2019). Firstly, naturally acquired antibodies against several gametocyte antigens, such as Pfs230, Pfs45/48, and the zygote/ookinete proteins Pfs25 and Pfs28, have been documented (Joice et al. 2014; Bousema et al. 2010). Secondly, CD8+ T cells and γδ T cells have been identified as playing roles in the body's immune response against gametocytes, with CD4+ T cells observed as the primary producers of cytokines TNF-α and IFN-γ, which directly target gametocytes (Ouedraogo et al. 2018; Good et al. 1987).

Naturally acquired antibodies against gametocyte antigens such as Pfs230, Pfs45/48, Pfs25, and Pfs28 target the parasite and help in neutralizing it (Joice et al. 2014). These antibodies can inhibit the development and maturation of the parasite within the red blood cells, thus reducing the severity and duration of the infection (Dantzler and Jagannathan 2018). CD8+ T cells are involved in killing infected host cells and may contribute to reducing the parasite load within the host (Akter et al. 2019). γδ T cells can respond to stress-induced ligands on infected cells and may contribute to controlling the infection early by recognizing and targeting parasite-infected cells (Villarino and Schmidt 2013). CD4+ T cells produce cytokines such as TNF-α and IFN-γ, which enhance the immune response by activating macrophages and other immune cells, thus helping to control and clear the infection (Ouedraogo et al. 2018; Good et al. 1987). Furthermore, antibodies against gametocyte antigens can block the transmission stages of the parasite by targeting gametocytes, preventing them from developing within the mosquito vector (Crotty 2014). This reduces the likelihood of the parasite being passed on to new hosts (Crotty 2014). Cytokines (TNF-α and IFN-γ) produced by CD4+ T cells create an inflammatory environment that can hinder gametocyte development and survival, thus reducing the number of mature gametocytes available for mosquito uptake (Ouedraogo et al. 2018; Good et al. 1987).

The role of different cells in response to P. falciparum infection

Both cell-mediated and humoral-mediated immune responses are crucial defense mechanisms against malaria, with early reliance on cell-mediated innate responses and the subsequent activation of antigen-specific T cells. Neutrophils, monocytes, and natural killer (NK) cells contribute to innate immunity during the initial stages of infection (Biswas et al. 2014; Lu et al. 2020). Additionally, natural killer T (NKT) cells have been identified as potent inhibitors of liver stage parasite replication in mouse malaria systems in vitro, implicating them in innate malarial immunity (Zhao et al. 2018).

Macrophages, monocytes and dendritic cells in P. falciparum infection

Macrophages are pivotal in removing infected red blood cells (iRBCs) from circulation through phagocytosis (Perlmann and Troye-Blomberg 2002). The importance of macrophages in protection against malaria is evident through their roles in phagocytosing pRBCs, presenting antigens, and producing cytokines (Vernes 1980). Classically activated (M1) macrophages are especially crucial for their parasiticidal activities, while alternatively activated (M2) macrophages help regulate inflammation (Ozarslan et al. 2019). Resident macrophages in the liver and spleen, along with monocyte-derived macrophages, also play significant roles in controlling the infection and maintaining immune homeostasis (Ozarslan et al. 2019). Understanding these diverse roles highlights the multifaceted contributions of macrophages to the immune defense against malaria (Ozarslan et al. 2019). Haemozoin, a polymerized form of heme and other soluble endotoxins released from ruptured schizonts, directly stimulates macrophages to produce TNF-α (Marsh and Kinyanjui 2006; Atri et al. 2018). Monocytes quickly ingest haemozoin, hindering their maturation and differentiation into dendritic cells (Nagao et al. 1996). Ingestion of iRBCs containing haemozoin suppresses further phagocytosis of iRBCs or other substrates. Moreover, haemozoin inhibits oxidative burst and Protein Kinase C (PKC) activity, significantly impairing the intracellular killing of pathogens by the generation of superoxide radicals (Ndungu et al. 2005; Schwarzer et al. 1993).

Dendritic cells (DCs) are essential for the initiation and regulation of the adaptive immune response against malaria (Urban and Roberts 2002). They are the primary antigen-presenting cells (APCs) responsible for priming CD4+ and CD8+ T cells (Urban and Roberts 2002). Different types of DCs, each with unique roles and mechanisms, are important for this process (Yap et al. 2019). Conventional Dendritic Cells 1 (cDC1) are particularly effective at cross-presenting antigens to CD8+ T cells, which is crucial for generating cytotoxic T lymphocyte (CTL) responses (Hasegawa and Matsumoto 2018). cDC1s express high levels of CD141 (BDCA-3) in humans. They excel at presenting antigens derived from intracellular pathogens, including the liver and blood stages of the malaria parasite (Fu and Jiang 2018). Conventional Dendritic Cells 2 (cDC2) are more adept at presenting antigens to CD4+ T cells, promoting helper T cell responses (Osii et al. 2020).

They express CD1c (BDCA-1) in humans. cDC2s are essential for activating Th1, Th2, and Th17 responses, which are vital for coordinating the immune response against different stages of the malaria parasite (Osii et al. 2020). Plasmacytoid Dendritic Cells (pDCs) pDCs are known for their ability to produce large amounts of type I interferons (IFNs) in response to viral infections, but they also play a role in bacterial and parasitic infections (Saito et al. 2022). They express CD303 (BDCA-2) in humans. Although their role in malaria is less well-defined compared to cDCs, pDCs can contribute to the immune response by activating T cells and producing cytokines that influence other immune cells (Ali et al. 2019). Monocyte-Derived Dendritic Cells (moDCs) arise from monocytes recruited to sites of infection and inflammation (Yap et al. 2019). They are particularly important in inflammatory settings and can efficiently present antigens to both CD4+ and CD8+ T cells. They bridge the innate and adaptive immune responses and are critical during severe malaria, where inflammation is pronounced (Yap et al. 2019). DCs capture malaria antigens through various receptors, such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and scavenger receptors. For example, TLR9 can recognize Plasmodium DNA, leading to DC activation (Shin et al. 2019). After capturing antigens, DCs process them and present peptide fragments on major histocompatibility complex (MHC) molecules: MHC class I for CD8+ T cell activation and MHC class II for CD4+ T cell activation (Shin et al. 2019).

Upon antigen uptake, DCs undergo maturation, characterized by the upregulation of surface markers such as CD80, CD86, and MHC molecules (Shin et al. 2019). Mature DCs also produce cytokines like IL-12, which is crucial for Th1 differentiation and IFN-γ production (Terrazas et al. 2010). Mature DCs migrate from peripheral tissues to lymph nodes via the expression of chemokine receptors like CCR7, facilitating the interaction with naïve T cells. In the lymph nodes, DCs present antigens to naïve T cells. The interaction between the T cell receptor (TCR) on T cells and the MHC-peptide complex on DCs, along with co-stimulatory signals (e.g., CD80/CD86 binding to CD28 on T cells), leads to T cell activation. For CD8+ T cells, cDC1s are particularly effective due to their cross-presentation capabilities, essential for generating CTLs that can target infected hepatocytes and erythrocytes (Hwang et al. 2020; León and Lund 2019). For CD4+ T cells, cDC2s are more involved, promoting various helper T cell responses necessary for coordinating B cell antibody production, macrophage activation, and cytokine-mediated regulation of immune responses (Hwang et al. 2020; León and Lund 2019). DC activation and function are tightly regulated by cytokines and interactions with other immune cells (Brandum et al. 2021). For instance, IL-10 can inhibit DC maturation and cytokine production, modulating the immune response to prevent excessive inflammation (Brandum et al. 2021). Regulatory T cells (Tregs) can also influence DC activity, promoting tolerance and preventing autoimmunity by producing immunosuppressive cytokines like IL-10 and TGF-β (Blanco et al. 2008).

Dendritic cells (DCs) serve as antigen-presenting cells (APCs) critical for initiating primary immune responses and potentially regulating T cell-mediated immune responses (Goswami et al. 2022). They have been implicated in the initiation of immune responses against malaria (Banchereau et al. 2000). Recent studies on P. yoelii have demonstrated that mature CD11c+ DCs prime CD8+ T cells in the skin-draining lymph nodes (Urban et al. 1999). Additionally, DCs are known to internalize Plasmodium antigens, process them, and present them to CD4+ T cells during the early stages of CD4+ T cell activation (Yap et al. 2019).

CD8+ T cells in P. falciparum infection

Previous research conducted in mouse models, non-human primates, and humans has consistently demonstrated that CD8+ T cells serve as the primary effector cells against pre-erythrocytic stages of various Plasmodium malaria species (Chakravarty et al. 2007). While exposure to sporozoites activates CD8+ T cells specific for antigens expressed in pre-erythrocytic stages in both humans and animals (Day and Marsh 1991), these cells are particularly crucial for eliminating parasites that invade and replicate within hepatocytes (Weiss and Jiang 2012). However, ethical limitations hinder the direct study of CD8+ T cells and other immune cells as anti-parasitic agents against P. falciparum malaria in humans, making mouse models a preferred option.

Studies have revealed that naïve CD8+ T cells lack the ability to exert anti-parasitic activity until they are primed by antigen-presenting cells (APCs) (Overstreet et al. 2008). Others have also demonstrated that CD8+ T cells are initially primed by mature CD11c+ dendritic cells in the skin-draining lymph nodes, as mentioned earlier (Urban et al. 1999). Unlike memory cells, naïve CD8+ T cells do not immediately eliminate parasitized cells upon antigen recognition; instead, they require a priming period of up to twenty-four hours. Once primed, these cells undergo differentiation and produce mediators such as IFN-γ and perforin, enabling them to eliminate malaria parasites during the liver stage (Holz et al. 2016). The proper development of a CD8+ T cell response is heavily reliant on CD4+ T cells whereby elimination of CD4+ T cells leads to a reduction of more than 90% in the CD8+ T cell response (Holz et al. 2016). IL-4, secreted by CD4+ T cells, is believed to be crucial for the complete development of the CD8+ T cell response, although other cytokines such as IL-2, IL-15, and IL-17 may also play significant roles (Sano et al. 2001).

Recent research indicates that primed CD8+ T cells differentiate into either short-lived effector cells (SLECs) or memory precursor effector cells (MPECs), depending on the cytokine environment and transcriptional factor profile (Cockburn et al. 2014). SLECs and MPECs then undergo clonal expansion in the presence of IL-2 or IL-4 produced by CD4+ T cells, leading to a notable increase in these cells following sporozoite inoculation (Douglas et al. 2014; Gomes et al. 2016). Subsequently, SLECs migrate to the liver to exert their effector functions, while MPECs undergo further differentiation to form species-specific memory CD8+ T cells (Obar et al. 2011).

Malaria-specific memory T cells (both CD8+ and CD4+ T cells) primarily engage in surveillance, continuous patrolling, and rapid recruitment to infection sites (Radtke et al. 2015), thus offering rapid, effective, specific, and durable protection against subsequent malaria infections. Further studies have described CD8+ T memory cells as liver-resident cells (TRM) or circulating effector cells (TEM), with effector responses of these subsets being species-specific (Reyes-Sandoval et al. 2011). Consistent with expectations from mouse studies, a significant proportion of circulating CD8+ T memory cells are TEM, with a smaller fraction being TCM (Joice et al. 2014; Bousema et al. 2010). Functionally, TEM induce effector functions, whereas TCM respond to sporozoite challenge with delayed IFN-γ production (Weiss and Jiang 2012; Reyes-Sandoval et al. 2011). Therefore, a higher population of TEM cells is necessary for effective long-term protection (Reyes-Sandoval et al. 2011). In contrast, TRM, a non-circulating subset, are associated with protection against sporozoite reinfection (Fernandez-Ruiz et al. 2016).

Recent in vitro studies indicate that the patrolling and effector activities of Plasmodium-specific tissue-resident memory T cells (TRM) rely on the interaction between Lymphocyte Function-Associated Antigen-1 (LFA1) and Intracellular Adhesion Molecule 1 (ICAM1) (Spencer et al. 2017). Therefore, despite their limited ability to recirculate, TRM cells are essential components of the initial protective response against malaria infection and play a critical role in recruiting other immune cells to the infection site (Spencer et al. 2017).

The precise effector mechanisms employed by CD8+ T cells to eliminate liver stage parasites are not yet fully elucidated, but several studies suggest that IFN-γ produced by CD8+ T cells exerts a potent inhibitory effect on malaria parasite development during the liver stage. CD8+ T cells recognize specific epitopes presented by MHC-I molecules on infected hepatocytes and form clusters around these cells (Perlmann and Troye-Blomberg 2002; Fernandez-Ruiz et al. 2016). Murine studies have demonstrated increased expression of CD8+ T cell effector molecules, including cytokines like IFN-γ and TNF-α, as well as TRAIL, FAS Ligand, and granzyme (Kurup et al. 2019). Furthermore, studies have shown that depletion of NK cells significantly diminishes the protective effect of CD8+ T cells, suggesting that NK cells serve as intermediaries for CD8+ T cells (McNamara et al. 2017). Overall, CD8+ T cells are pivotal in the immune defense against P. falciparum, primarily by targeting and eliminating liver-stage parasites. Their cytotoxic activity, cytokine production, and the development of memory cells contribute to both immediate and long-term protection. The ability to harness and enhance CD8+ T cell responses is a critical focus in malaria vaccine development and in strategies aimed at achieving effective and durable immunity against malaria (McNamara et al. 2017).

CD4+ T cells in P. falciparum infection

In humans, CD4+ T cells are essential for regulating the immune response to P. falciparum infection, as they have been observed to inhibit parasite growth in vitro (Bonam et al. 2021). In vitro stimulation of CD4+ T cells with P. falciparum malaria antigens induces proliferation of CD4+ T cells from individuals with no previous exposure to malaria infection, along with secretion of IFN-γ (Fell et al. 1996). Interestingly, these responses did not positively correlate with serum antibody levels against the corresponding antigens (Goodier and Targett 1997). In contrast, P. falciparum antigen-stimulated secretion of IL-4 by CD4+ T cells did not correlate with lymphocyte proliferation or IFN-γ release but did correlate with concentrations of relevant serum antibodies (Rzepczyk et al. 1989). These observations suggest that distinct subsets of CD4+ T cells, corresponding to Th1 and Th2 cells, regulate the human immune response to malaria infection, with both helper and effector functions contributing to malaria immunity (Troye-Blomberg et al. 1990).

CD4+ T cells are crucial for helping B cells produce antibodies. They provide necessary signals, such as cytokines and surface interactions (e.g., CD40L-CD40), that promote B cell activation, proliferation, and differentiation into plasma cells that secrete specific antibodies against malaria antigens (Stephens and Langhorne 2006). These antibodies can neutralize the parasite, opsonize infected red blood cells (RBCs) for phagocytosis, and block parasite invasion into new RBCs. They also produce cytokines that enhance the innate immune system's phagocytic and parasiticidal responses while regulating this response to limit immunopathology (Elgueta et al. 2009). Additionally, CD4+ T cells contribute to protective immunity against malaria liver stages by directly inhibiting parasite development and supporting the function of CD8+ T cells (Beverley 1990). Moreover, CD4+ T cell clones derived from peripheral blood mononuclear cells (PBMCs) respond not only to P. falciparum antigens but also to various bacterial, viral, and fungal preparations upon stimulation, suggesting the maintenance of memory T cells through cross-reactive stimulation (Elgueta et al. 2009).

A specific subset of CD4+ T cells known as T follicular helper cells (Tfh) has been identified as crucial players in malaria infection (Urban and Roberts 2003). Tfh cells express markers such as Bcl6, CXCR5, PD-1, ICOS, SAP, CD40L, TCF-1, and PSGL1, with CXCR5 serving as a well-known B-cell zone homing marker (Hansen et al. 2017). Circulating distinct subsets of Tfh cells (cTfc) have been detected in human peripheral blood (Crotty 2019). Studies in mouse models have highlighted the requirement of CD4+ T cell intrinsic Bcl6 signaling and cytokines such as IL-6 and IL-21 for Tfh responses induction, while the presence of Type 1 IFN tends to compromise Tfh cells and Tfh-mediated germinal center responses (Morita et al. 2011; Pérez-Mazliah et al. 2017). Notably, activation of Th2-cTfh cells during P. falciparum malaria infection correlates with the development of functional antibodies required for protective immunity in humans (Sebina et al. 2016).

Tfh cells are potent inducers of antibody production, activating B cells within germinal centers to generate high-affinity antibodies and memory B cell responses (Chan et al. 2020). These memory B cells subsequently give rise to long-lived plasma cells, which maintain circulating antibodies in various diseases, including malaria (Yu et al. 2009). The relationship between Tfh cells and long-lived plasma cells makes Tfh cells an ideal target for improving vaccine efficacy (Nurieva et al. 2009). Studies in mouse models of malaria infection have shown that malaria inhibits the establishment of germinal centers in the spleen and leads to impaired Tfh cell differentiation, but restoration of Tfh cell differentiation and germinal center responses can be achieved by blocking TNF, IFN-γ, or deleting Tbet (Linterman and Hill 2016; Ryg-Cornejo et al. 2016). Other human studies have reported activation of cTfh cells during acute P. falciparum malaria, with increased expression of activation markers observed, particularly in Th1-cTfh subsets (Obeng-Adjei et al. 2015). Given the crucial role of Tfh cells in antibody development, some suggest targeting this CD4+ T cell subset to enhance vaccine efficacy (Nurieva et al. 2009). A recent study demonstrated that early induction of functional IL-21-secreting CSP-specific peripheral Tfh cell subset contributes to improved efficacy of RTS,S/AS01 when employing a delayed fractional dose (DFD) schedule (Obeng-Adjei et al. 2015).

Th1 CD4+ T cells subset, produce cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). IFN-γ activates macrophages, enhancing their ability to kill intracellular parasites and phagocytose infected RBCs. TNF-α contributes to inflammation and helps control parasite replication but needs to be tightly regulated to prevent excessive pathology (Pallikkuth et al. 2020). Th2 cells produce cytokines like IL-4 and IL-10, which can help modulate the immune response, support B cell antibody class switching, and aid in the regulation of inflammation (Long and Graham 2011). CD4+ T cells also produce regulatory cytokines that help balance the immune response, preventing excessive inflammation and potential tissue damage. Through the production of IFN-γ, CD4+ T cells activate macrophages, enhancing their ability to phagocytose and destroy parasitized RBCs (Vazquez et al. 2015). This is critical for controlling the parasite load during the blood stage of infection. Furthermore, CD4+ T cells help prime and activate CD8+ T cells by providing essential cytokines and creating an environment conducive to CD8+ T cell activation. Activated CD8+ T cells can then target liver-stage parasites and contribute to the reduction of the parasite reservoir (Artavanis-Tsakonas et al. 2003). A subset of CD4+ T cells, Tregs, helps regulate the immune response by producing anti-inflammatory cytokines like IL-10 and TGF-β. This regulation is crucial to prevent immunopathology and maintain a balanced immune response that can clear the infection without causing excessive tissue damage (Morrot and Rodrigues 2014).

In general, CD4+ T cells are essential for a robust and effective immune response against P. falciparum. They facilitate the production of antibodies, activate macrophages, support CD8+ T cell functions, and regulate immune responses to prevent pathology (Panetti et al. 2022). The balance they provide is critical for controlling parasite replication, aiding in the clearance of infected cells, and ensuring long-term immunity (Panetti et al. 2022). Understanding the specific roles and mechanisms of CD4+ T cells in malaria can help in designing effective vaccines and immunotherapies to combat this disease.

Gamma/delta (γδ) T cells in P. falciparum infection

Gamma delta T (γδ T) cells are typically seen as a link between the innate and adaptive immune responses due to their reaction to infection (Vermare et al. 2022). In experiments where mice lacked αβ T cells and were vaccinated via bites from irradiated Plasmodium-infected mosquitoes, they displayed a partial protective response against sporozoite challenge (Latha et al. 2014). However, when γδ T cells were removed from these mice, the protective immunity was significantly reduced, indicating that γδ T cells possess the ability to hinder parasite development during the liver stage and contribute to protective immunity in these mice (Latha et al. 2014). Gamma/delta T cells therefore have a role in response to both pre-erythrocytic stage parasites and blood-stage parasites. Notably, the Vγ9Vδ2 subset of γδ T cells has been observed to increase in proportion and numbers in individuals displaying malaria symptoms, with the highest proportions seen in severe malaria cases (Tsuji et al. 1994). In vitro stimulation of γδ T cells with malaria antigens leads to proliferation and production of cytokines such as IFN-γ, IL-1β, and TNF-α, which have been linked to protection against malaria disease (Taniguchi et al. 2017).

γδ T cells are likely activated during malaria infection through recognition of non-peptide antigens, stress-induced ligands, and cytokine signals (Jones et al. 1996). In vivo evidence from human studies demonstrates that γδ T cells exert protective effects through cytotoxic activity against infected cells, production of key cytokines like IFN-γ and TNF-α, modulation of αβ T cell responses, and interactions with dendritic cells. These mechanisms collectively contribute to the control of parasite growth and the coordination of an effective immune response against P. falciparum infection (Dantzler and Jagannathan 2018).

B cells in P. falciparum infection

B cell activation and the development of distinct B cell subsets play critical roles in the immune response to malaria infection (Schönefeldt et al. 2021). The complex interaction between the malaria parasite and the host immune system involves several mechanisms aimed at both controlling the infection and contributing to immunity (Schönefeldt et al. 2021). B cells are activated upon recognizing specific malaria antigens presented by the Plasmodium parasites (Kalkal and Das 2023). This typically occurs in the spleen and other secondary lymphoid organs. B cell activation requires help from T follicular helper (Tfh) cells. These cells provide necessary signals through CD40L-CD40 interactions and cytokines like IL-21, which promote B cell proliferation and differentiation (Kalkal and Das 2023). Once activated, B cells migrate to germinal centers within lymphoid organs where they undergo somatic hypermutation and class-switch recombination, processes crucial for affinity maturation and the production of high-affinity antibodies. Within GCs, B cells are selected based on their affinity for the antigen. High-affinity B cells differentiate into long-lived plasma cells or memory B cells (Kalkal and Das 2023; Silveira et al. 2018).

Short-Lived Plasma Cells are generated early during infection and produce a rapid but short-lived antibody response whilst Long-Lived Plasma Cell reside in the bone marrow and continuously secrete high-affinity antibodies, providing long-term immunity (Yue et al. 2022). Furthermore, memory B cells are critical for long-term protection and can rapidly respond to subsequent malaria infections by differentiating into antibody-secreting plasma cells upon re-exposure to the parasite (Bortnick and Allman 2013). There is also Atypical Memory B Cells (AtMBCs) which exhibit an exhausted phenotype with markers such as FCRL5, CD21 and CD27 (Ly and Hansen 2019). They have been found in higher frequencies in individuals with chronic or repeated malaria exposure (Ly and Hansen 2019). The exact role of AtMBCs in malaria is still under investigation, but they are thought to be less effective in mounting an immune response compared to classical memory B cells (Ly and Hansen 2019). Their presence is often associated with chronic infections and could represent a state of immune dysfunction or adaptation. There is also Regulatory B Cells (Bregs) which produce immunosuppressive cytokines like IL-10 and can modulate immune responses to limit excessive inflammation and tissue damage during infection. Their role in malaria is not fully understood but is believed to be part of the regulatory network that controls immune responses (Sullivan et al. 2015).

The Plasmodium parasites exhibit extensive antigenic variation, which helps them evade the host immune system. This variation poses a challenge for the development of effective B cell responses and long-lasting immunity (Chekol Abebe et al. 2021). This is because malaria can induce a state of immune suppression, affecting the function and activation of B cells (Chekol Abebe et al. 2021). This suppression can be mediated by regulatory T cells, cytokines, and the direct effect of parasitic molecules (Chekol Abebe et al. 2021). Severe malaria is often associated with a transient reduction in lymphocyte counts, including B cells, which can impair the immune response (Ezema et al. 2023). In fact, B cells are essential for the humoral immune response to malaria, involving complex activation pathways and the formation of various subsets that contribute to immediate and long-term immunity (Ezema et al. 2023). Understanding these processes is critical for developing effective malaria vaccines and therapeutic strategies.

Natural killer (NK) cells in P. falciparum infection

NK cells, a subset of lymphocytes, exhibit effector functions akin to cytotoxic T lymphocytes and serve as a crucial frontline defense against pathogens. Their ability to act without prior sensitization to antigens makes them pivotal in combating infections (Gómez-Pérez et al. 2014). During malaria infection, NK cell numbers increase, and they demonstrate the capacity to lyse P. falciparum-infected erythrocytes in vitro (Ndwiga et al. 2021; Trinchieri 1989).

While traditionally associated with the innate immune system, recent evidence suggests that NK cells may also contribute to antigen-specific acquired immunity to P. falciparum malaria. These cells, along with T cells, are major producers of IFN-γ, particularly when stimulated by IL-12 in parasitic and bacterial models, which is essential for protective immunity (Trinchieri 1989). NK cells are distributed in the blood, secondary lymphoid organs, and peripheral non-lymphoid tissues. In non-immune individuals, NK cells are among the first responders in peripheral blood to produce IFN-γ upon encountering P. falciparum-infected erythrocytes (Zhao et al. 2018). Additionally, direct recognition of P. falciparum infection by NK cells triggers their production of the pro-inflammatory chemokine IL-8, indicating their involvement in recruiting and activating other immune cells during malaria infection (Trinchieri 1989).

NK cells are not only activated by cytokines but also mediate their activities through stimulation of activating receptors and the direct lysis of infected cells (Roetynck et al. 2006). In the liver stage of malaria, NK cells target infected hepatocytes through both cytokine-mediated activation and direct recognition of stress-induced ligands on infected cells (Roetynck et al. 2006). During the blood stage, NK cells recognize and lyse antibody-coated pRBCs via CD16 and produce cytokines like IFN-γ to activate macrophages and other immune cells. Thus, NK cells play a multifaceted role in both the liver and blood stages of malaria infection, contributing to the control and clearance of the parasite (Freeman et al. 2015).

Regulatory T cells in P. falciparum infection

CD4+CD25+ T cells represent a specialized subset of T cells tasked with controlling immune responses to prevent excessive activation. They possess the ability to curtail the activation, proliferation, and effector functions of both CD4+ and CD8+ T cells (Capuano et al. 2021). Regulatory T cells are distinguished by their elevated expression of the transcription factor Foxp3, setting them apart from conventional CD4+ T cells. In the context of experimental malaria, these cells have emerged as key players in immune regulation (Boehmer 2005). Studies have demonstrated in increased proportions at various stages of human P. falciparum malaria (Hisaeda et al. 2004).

Both Foxp3+ Tregs and Tr1 cells are vital in preventing immune-mediated pathology during malaria infection (Frimpong et al. 2018). They do so by producing regulatory cytokines such as IL-10 and TGF-β, these cells modulate the immune response to prevent excessive inflammation and tissue damage, which are common in severe malaria cases (Frimpong et al. 2018). These regulatory cells help maintain a balance between effective parasite clearance and the prevention of immunopathology (Frimpong et al. 2018). This balance is crucial for the host to control the infection while avoiding detrimental effects of an overactive immune response (Frimpong et al. 2018). By preventing excessive immune responses, Foxp3+ Tregs and Tr1 cells help preserve the integrity of the immune system, allowing for the development of long-term immunity (Nideffer and Jagannathan 2023). This is important for sustained protection against future malaria infections. In summary, Foxp3+ Tregs and Tr1 cells play critical roles in regulating the immune response during malaria infection (Nideffer and Jagannathan 2023). They help prevent excessive inflammation and tissue damage, balance effective parasite clearance with immune regulation, and ensure long-term immunity (Freeborn et al. 2022). Their functions are essential for controlling the infection and preventing severe disease outcomes.

The role of other immune factors in P. falciparum infection

Cytokines

Cytokines, which are polypeptides derived from cells and play a crucial role in inflammation, are vital in determining cellular activation and systemic responses during inflammation. These multifunctional factors exert their effects either locally or systemically through autocrine or paracrine pathways (Obeagu 2024). They are produced by a wide array of cells including lymphocytes, monocytes, macrophages, fibroblasts, neutrophils, endothelial cells, and mast cells (Feghali and Wright 1997). Cytokines have been identified as significant factors influencing malaria severity and its outcome (Jason et al. 2001). Some researchers propose that the balance between pro-inflammatory cytokines (such as TNF-α, IFN-γ, IL-6, and IL-8) and anti-inflammatory cytokines (like IL-4 and IL-10) plays a crucial role in determining malaria parasitaemia, level of anaemia, clinical severity, presentation, and ultimate outcome (Grau et al. 1989).

Antibodies

Antibodies play a critical role in safeguarding against malaria, as evidenced by experiments demonstrating that transferring immunoglobulins from adults immune to malaria to individuals lacking immunity provides passive protection (Kossodo and Grau 1993). This protection extends even to infants under six months of age, who benefit from maternal antibodies (Sabchareon et al. 1991). Functioning as the first line of defense, antibodies target a variety of antigens expressed by different stages of the parasite in the blood. They counter sporozoites invading the liver, hinder merozoites from infecting red blood cells, and facilitate the uptake of merozoites by phagocytes through opsonization and antibody-dependent cellular inhibition (Kurtis et al. 2019; Egan et al. 1999).

Research examining the protective effects of antibodies targeting merozoites has yielded varied outcomes (Joos et al. 2010). While some studies support the role of specific antibodies in protection, others show little evidence for their effectiveness or even suggest an increased risk of symptomatic malaria (Stanisic et al. 2009). These discrepancies may stem from differences in study design, including participant age, malaria transmission rates, and population immunity levels (Stanisic et al. 2009). Recent investigations have compared the dynamics of anti-merozoite IgM and IgG following both experimental and natural malaria infections. They found that IgM persists in both young children and adults, akin to IgG, and likely contributes to protection by blocking merozoite invasion of red blood cells in a complement-dependent manner (Greenhouse et al. 2019).

In populations where antibody levels haven't yet reached a point of predictive clinical immunity, antibody levels closely correlate with recent malaria exposure. Consequently, they serve as promising biomarkers of malaria risk, aiding in the identification of individuals with the greatest exposure to Plasmodium infection (Bisoffi et al. 2020). Specific antibodies targeting merozoite antigens, for instance, have undergone extensive investigation as potential serological biomarkers of P. falciparum exposure or as indicators of immunity, facilitating the monitoring of shifts in malaria transmission patterns over time (Stanisic et al. 2015).

Antibody responses to blood-stage malaria play a crucial role in inhibiting parasite invasion, thus curtailing cytoadherence and sequestration to vascular endothelium (Fernandez-Ruiz et al. 2016; Richards et al. 2013). This inhibition is achieved by binding to parasite adhesion molecules (PfEMP-1) on the surface of infected red blood cells (iRBCs). Additionally, antibodies neutralize parasite toxins like GPI, thereby dampening the inflammatory response. They also thwart the fertilization of gametes, the production of zygotes, and induce the killing of extracellular gametes (Egan et al. 1999). During acute malaria episodes, antibodies against P. falciparum blood stages consistently emerge and rapidly increase in concentration. These notable fluctuations in antibody levels suggest a potential new approach to malaria screening, wherein a decline in antibody titers, alongside molecular diagnostics, may signal waning immunity against malaria (Greenhouse et al. 2019).

General fate of white blood cells due to P. falciparum infection

Plasmodium falciparum, has a profound impact on the host's immune system, particularly on white blood cells (McQueen and McKenzie 2008). The interaction between P. falciparum and the host immune system results in various changes in the number, function, and fate of different types of white blood cells (McQueen and McKenzie 2008). During acute P. falciparum infection, there is often a marked decrease in the number of circulating lymphocytes (Acquah et al. 2020). This reduction affects both T cells and B cells and is associated with the sequestration of these cells in the spleen and other lymphoid tissues. Again, in response to P. falciparum infection, there is typically an increase in the number of neutrophils (Acquah et al. 2020). Neutrophils play a crucial role in the initial immune response by phagocytosing infected erythrocytes and releasing reactive oxygen species and other antimicrobial agents (Acquah et al. 2020).

Monocytes, which can differentiate into macrophages and dendritic cells, often increase in number during malaria infection. These cells are important for phagocytosing infected erythrocytes, presenting antigens to T cells, and producing pro-inflammatory cytokines (Hviid and Kemp 2000). The dysregulation of white blood cell responses, including lymphopenia, excessive inflammation, and immune suppression, is associated with severe malaria, characterized by complications such as cerebral malaria, severe anaemia, and multi-organ failure (Hirayama et al. 2017). Also, understanding how P. falciparum affects white blood cell function is crucial for developing effective vaccines. Strategies that enhance protective immune responses while avoiding excessive inflammation and immune suppression are needed. Subsequently, P. falciparum infection leads to significant changes in the number and function of white blood cells, including lymphopenia, neutrophilia, and monocytosis (Perkins et al. 2011). These changes are part of the complex interplay between the parasite and the host immune system, contributing to both the control of the infection and the pathology associated with malaria (Kini and Chandrashekhar 2016).

Research suggests that Fas-induced apoptosis plays a significant role in the lymphopenia observed in P. falciparum malaria in humans and in Plasmodium coatneyi-infected macaques (Mawson 2013). Both studies draw their conclusions from concurrent observations of elevated levels of soluble Fas ligand in serum and lymphopenia. A key aspect supporting their arguments is the discovery of spontaneous ex vivo T-cell apoptosis in P. falciparum patients from Senegal (Kern et al. 2000). However, there are no other reports corroborating the hypothesis that high levels of apoptotic cells in peripheral blood are a consistent feature of P. falciparum malaria. Lymphopenia is a well-established characteristic of P. falciparum malaria but is replaced by lymphocytosis within a few days of initiating drug therapy, gradually returning to normal over the subsequent weeks (Toure-Balde et al. 1996). It is challenging to reconcile this occurrence if lymphopenia results from widespread apoptosis. Instead, it has been proposed that initial lymphopenia reflects the disease-induced relocation of T cells to sites of inflammation, followed by their reappearance upon recovery (Wolfswinkel et al. 2013).

Conclusion

In conclusion, the host immune response to malaria represents a multifaceted interaction between Plasmodium and the human immune system (Hviid et al. 1997). From the initial encounter with the parasite, innate immune mechanisms swiftly mobilize to recognize and initiate a response against the invader (Hviid et al. 1997). This is followed by a coordinated adaptive immune response, spearheaded by T and B lymphocytes, which work in tandem to target and eliminate the parasite (Belachew 2018). While the immune system's efforts are remarkable, the complexity of malaria and its ability to evade host defenses present significant challenges (Good et al. 2005). Factors such as parasite diversity, host genetics, and prior exposure influence the development of protective immunity, with some individuals achieving partial protection while others remain susceptible to severe disease (Sebina et al. 2016). Moving forward, a comprehensive understanding of the host immune response to malaria is imperative for the development of effective interventions.

It is important to also mention that investigators are now employing much more sophisticated technologies and systems immunology to investigate protective responses to malaria parasites, marking a transformative era in malaria research (Alberts et al. 2002b). Advances in molecular and immunological techniques are providing unprecedented insights into the complex interactions between the malaria parasite and the host immune system (Alberts et al. 2002b). High-throughput sequencing, proteomics, and advanced imaging technologies allow for detailed characterization of parasite antigens and host responses at a molecular level (Galinski 2022). Systems immunology integrates these data through computational models, enabling researchers to decipher the intricate networks governing immune protection and pathogenesis (Alberts et al. 2002b). These cutting-edge approaches are enhancing our understanding of immune memory, identifying novel vaccine targets, and optimizing strategies for effective malaria vaccines, ultimately driving progress towards malaria eradication.

Declarations

Conflict of interest

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. The Authors declare that there is no conflict of interest.