**6. Mechanisms of immune evasion by malaria parasites**

Like other parasites, malaria parasites are not passive partners in the interaction with the host immune system. The immune system exerts a strong selective pressure on malaria parasites. They have therefore over time evolved a number of mechanisms to evade the immune system.

Polymorphism is a common feature of many malaria antigens and is generated through recombination during fertilization or clonal antigenic variation (Anders and Smythe 1989, Borst *et al* 1995). The circumsporozoite protein (CSP) (Dame *et al* 1984, Lockyer *et al* 1989) and thrombospondin–related adhesive protein (TRAP) (Robson *et al* 1998) on the surface of sporozoites all have regions of extensive polymorphism as does the major merozoite antigens; merozoite surface proteins (MSP-2 & MSP-2) (Cooper 1993, Felger *et al* 1994), ring stage erythrocyte surface antigen (RESA) (Perlmann *et al* 1984) and the apical membrane antigen-1 (AMA-1) (Verra and Hughes 1999).

The antigens inserted by mature parasites on to the surface of the host red cells, which include PfEMP1, rifins, and STEVOR, not only exhibit extensive polymorphism between isolates from different patients, they also under go clonal variation so that each new generation of parasites exhibits different variant from the previous one (Bachmann *et al* 2011, Baruch *et al* 1995, Blythe *et al* 2004, Chen *et al* 1998, Cheng *et al* 1998, Niang *et al* 2009). In many instances, there is little immunological cross reactivity between different

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polymorphic variants of the same antigens meaning that encounter with parasites bearing one variant does not generate protection against infections bearing a different variant.

Some of the proteins in the parasite have not evolved a high level of polymorphism instead parasites escapes immune responses directed against these proteins through functional redundancy. In other words, the parasites are able to utilise more than one protein to achieve the same function. This is particularly the case for proteins involved in essential functions such as invasion of the red cell. The erythrocyte binding ligand (EBL) and the reticulocyte binding homologues (RH) protein families, (Adams *et al* 2001, Reiling *et al* 2010, Triglia *et al* 2009) both involved in invasion, consist of four and five closely related, but not identical, proteins respectively. Blocking invasion mediated by one of these protein results in a shift toward invasion pathways mediated by the other proteins (Lobo *et al* 2006, Lopaticki *et al* 2011, Persson *et al* 2008).

There is some evidence to suggest that apart from escaping immune recognition, malaria parasites can actively subvert the immune system and may direct it towards less effective responses. Some malaria antigens such as glycosylphosphatidylinositol (GPI) contain sections of tandem amino acid repeats in their structure. Such polymeric structures can cross-link B-cell antigen receptors and induce T-cell independent antibody production that is characterised by IgM dominance and poor affinity maturation and memory cells induction (Garcia de Vinuesa *et al* 1999). Besides being short-lived and ineffective, T-cell independent responses can also thwart protective responses to adjacent critical epitopes through epitopic inhibition (Schofield 1991). Disruption of splenic architecture, which prevents the formation of germinal centres and that could also lead to T-cell independent responses, has been observed in animal malaria model (Achtman *et al* 2003). Malaria parasites have been shown to prevent the maturation of dendritic cells through binding of infected red cells to dendritic cells using parasite generated variant surface antigens (Urban *et al* 1999, Urban *et al* 2001). However, other studies suggest that dendritic cell inhibition could also be mediated through other interactions not involving surface antigens (Elliott *et al* 2007). Furthermore, studies in mouse models suggest that the parasite –induced defect in maturation does not necessarily affect dendritic cells ability to induce protection in vivo (Pouniotis *et al* 2004). Recently it has been suggested that malaria parasite use the activation of regulatory T cells that suppress antiparasite cytokines production as a way of escaping the immune system. Mice whose T regulatory cells are depleted can survive infection with a lethal strain of *P. yoelii* and exhibit increased T-cell responsiveness to parasite antigens compared to normal mice (Hisaeda *et al* 2004).

## **7. Conclusions**

Although research has contributed significantly in our understanding of immunity towards malaria, there are still considerable gaps in our knowledge. Closing these gaps in order to facilitate the development of malaria vaccines remains one of the major goals of tropical diseases research. Two areas are key to developing a comprehensive picture of the interaction between the malaria parasites and the immune system: first there is need to standardise current methods for studying immunity to malaria in order to address the numerous inconsistencies concerning the efficacy of various response to malaria often encountered in the literature. Second there is need to take advantage of the advances in molecular biology in studying immunity to malaria for example use of high throughput

polymorphic variants of the same antigens meaning that encounter with parasites bearing one variant does not generate protection against infections bearing a different variant.

Some of the proteins in the parasite have not evolved a high level of polymorphism instead parasites escapes immune responses directed against these proteins through functional redundancy. In other words, the parasites are able to utilise more than one protein to achieve the same function. This is particularly the case for proteins involved in essential functions such as invasion of the red cell. The erythrocyte binding ligand (EBL) and the reticulocyte binding homologues (RH) protein families, (Adams *et al* 2001, Reiling *et al* 2010, Triglia *et al* 2009) both involved in invasion, consist of four and five closely related, but not identical, proteins respectively. Blocking invasion mediated by one of these protein results in a shift toward invasion pathways mediated by the other proteins (Lobo *et al* 2006,

There is some evidence to suggest that apart from escaping immune recognition, malaria parasites can actively subvert the immune system and may direct it towards less effective responses. Some malaria antigens such as glycosylphosphatidylinositol (GPI) contain sections of tandem amino acid repeats in their structure. Such polymeric structures can cross-link B-cell antigen receptors and induce T-cell independent antibody production that is characterised by IgM dominance and poor affinity maturation and memory cells induction (Garcia de Vinuesa *et al* 1999). Besides being short-lived and ineffective, T-cell independent responses can also thwart protective responses to adjacent critical epitopes through epitopic inhibition (Schofield 1991). Disruption of splenic architecture, which prevents the formation of germinal centres and that could also lead to T-cell independent responses, has been observed in animal malaria model (Achtman *et al* 2003). Malaria parasites have been shown to prevent the maturation of dendritic cells through binding of infected red cells to dendritic cells using parasite generated variant surface antigens (Urban *et al* 1999, Urban *et al* 2001). However, other studies suggest that dendritic cell inhibition could also be mediated through other interactions not involving surface antigens (Elliott *et al* 2007). Furthermore, studies in mouse models suggest that the parasite –induced defect in maturation does not necessarily affect dendritic cells ability to induce protection in vivo (Pouniotis *et al* 2004). Recently it has been suggested that malaria parasite use the activation of regulatory T cells that suppress antiparasite cytokines production as a way of escaping the immune system. Mice whose T regulatory cells are depleted can survive infection with a lethal strain of *P. yoelii* and exhibit increased T-cell responsiveness to parasite antigens

Although research has contributed significantly in our understanding of immunity towards malaria, there are still considerable gaps in our knowledge. Closing these gaps in order to facilitate the development of malaria vaccines remains one of the major goals of tropical diseases research. Two areas are key to developing a comprehensive picture of the interaction between the malaria parasites and the immune system: first there is need to standardise current methods for studying immunity to malaria in order to address the numerous inconsistencies concerning the efficacy of various response to malaria often encountered in the literature. Second there is need to take advantage of the advances in molecular biology in studying immunity to malaria for example use of high throughput

Lopaticki *et al* 2011, Persson *et al* 2008).

compared to normal mice (Hisaeda *et al* 2004).

**7. Conclusions** 

sequencing and DNA and protein microarray technology to facilitate the simultaneous study of the large range of responses evoked by a malaria infection or the development transgenic animal and parasite models that approximate better to malaria infections in human.

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**11** 

*USA* 

**The Impact of Immune Responses** 

**on the Asexual Erythrocytic Stages** 

**of** *Plasmodium* **and the Implication** 

Elke S. Bergmann-Leitner, Elizabeth H. Duncan and Evelina Angov *Department of Molecular Parasitology, Division of Malaria Vaccine Development,* 

Natural immunity against malaria is acquired after repeated infections for an extended period of time resulting in a state of immunological non-responsiveness against the malaria parasite. This state ultimately prevents the onset of severe disease such as cerebral malaria thereby reducing the risk of death from malaria. Individuals with acquired natural immunity to malaria still harbor parasites (albeit in low densities) in the blood, and therefore natural immunity against malaria is not sterile. For this reason, natural immunity to malaria cannot be compared to immunity achieved against other diseases where the immune response neutralizes and eliminates the pathogen. The second hallmark of natural immunity to malaria is that protection wanes once a "protected" individual leaves the malaria-endemic area indicating that protection depends on continued antigen exposure. Immunity to malaria is stage- and species-specific and distinct immune mechanisms confer protection against the different developmental stages of the parasite. In the case of blood stage infection, passive transfer experiments with purified human immunoglobulins derived from immune individuals living in malaria-endemic areas have demonstrated that antibodies can mediate protection (Cohen et al., 1961; Butcher et al., 1970; Bouharoun-Tayoun et al., 1990). Mechanistic studies revealed that the effect of blood stage-specific antibodies on the asexual erythrocytic parasite depends on their antigen-specificity; antibodies can bind to merozoites, opsonize and target them towards phagocytic cells of the host (Groux and Gysin, 1990), or prevent invasion of new erythrocytes (Perkins, 1991). Once infected, antibodies against asexual blood stage antigens such as Pf332 or MSP-1 inhibit the intra-erythrocytic development of *Plasmodium falciparum* (Ahlborg et al., 1996; Siddique et al., 1998; Bergmann-Leitner et al., 2009). Antibodies directed to antigens expressed by sexual erythrocytic stages (gametocytes) have been shown to prevent transmission of malaria by blocking either the infection of the mosquito or the development in the mosquito (Lavazec and Bourqouin, 2008). As will be outlined in this chapter, it becomes increasingly clear that a blood stage vaccine may never be able to induce sterile protection, but can prevent mortality. Why bother developing blood stage vaccines? Extensive studies characterizing

**1. Introduction** 

**for Vaccine Development** 

*Walter Reed Army Institute of Research,* 

