Antigenic variation in Plasmodium falciparum : Erythrocyte invasion and immune escape mechanisms

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Leo O’Neal’
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1 Antigenic variation in Plasmodium falciparum : Erythrocyte invasion and immune escape mechanisms

2 Introduction Why does immunity to malaria take so long to develop? The parasite s survival depends on its ability to persist in the human host and to be transmitted. coadaptation in which both evasion and impairment of the host immune system by P. falciparum lead to the slow and incomplete development of immunity How does Plasmodium falciparum evade the immune response? 2 forms of antigenic variability ANTIGENIC VARIATION : The antigenic changes that can occur within a parasite clone through switching the expression of different variant genes. ALLELIC POLYMORPHISM : Multiple forms of a gene at a single genetic locus.

coadaptation in which both evasion and impairment of the host immune system by P.

3 Erythrocyte invasion by P.falciparum merozoites 1) Initial attachment MSP-1 (merozoite surface protein-1) 2) Apical reorientation AMA-1 (apical membrane antigen-1) 3)Tight junction formation EBAs (erythrocyte binding antigens) PfRhs (P.falciparum reticulocyte-binding homologs)

protein-1) 2) Apical reorientation AMA-1 (apical membrane antigen-1)

4 Erythrocyte invasion by P.falciparum merozoites

5 Variant surface molecules Variant molecules expressed on merozoites Variant molecules expressed at the surface of infected erythrocytes (IEs)

6 Variant merozoite proteins Variant invasion-related ligands Two variantly expressed invasion ligands families : EBA and PfRh Ligand polymorphism Receptor-ligand interactions involved in junction formation

7 Variant merozoite proteins Alternative invasion pathways Variation in expression and/or use of EBA and PfRh proteins Invasion phenotypes : Sialic acid-dependent (SA-dependent) EBA175, EBA140, EBA181, and PfRh1 Sialic acid-independent (SA-independent) PfRh4 and PfRh2b. Classification based on invasion into enzyme-treated erythrocytes or mutant erythrocytes deficient for specific surface receptors. Neuraminidase sialic acid Trypsin glycophorin A,C,.. Chymotrypsin glycophorin B,

8 Variant merozoite proteins Alternative invasion pathways Characterization of the invasion phenotypes of different P.falciparum lines What is the molecular basis of switching to SA independent invasion?.

9 Variant merozoite proteins Alternative invasion pathways Activation of the PfRh4 gene is essential for the parasite to switch to SAindependent invasion Disruption of PfRh4 blocks the ability to switch from SA-dependent to SAindependent invasion Disruption of the EBA175 gene switch from SA-dependent to SAindependent invasion, associated with activation of PfRh4 expression SA-dependent invasion EBA175 PfRh4 SA-independent invasion

SA-dependent to SAindependent invasion Disruption of the EBA175 gene switch from SA-dependent to

10 Variant merozoite proteins Variant-specific immunity Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies Kristina E.M. Persson The Journal of Clinical Investigation. January 2008 Acquisition of inhibitory antibodies against SA-dependent invasion (EBA175) Acquisition of inhibitory antibodies against SA-independent invasion (PfRh4, PfRh2b) Naturally acquired Abs inhibit invasion by two isogenic parasite lines using different invasion pathways Normal erythrocyes Nm-treated erythrocyes EBA and PfRh ligands are the major targets of invasion-inhibitory Abs Inhibition of SA-dependent invasion Inhibition of SA-independent invasion

January 2008 Acquisition of inhibitory antibodies against SA-dependent invasion (EBA175) Acquisition of inhibitory antibodies against SA-independent invasion (PfRh4, PfRh2b)

11 Variant merozoite proteins Biological role of variant expression of invasion ligands adaptation to host immune selection adaptation to erythrocyte diversity Erythrocytes at different stages of maturity Mutant erythrocytes adaptation to polymorphisms in erythrocyte receptors immune evasion parasite survival Control of parasitemia Minimize the risk for severe malaria symptoms Chronic low-grade infection Reduced impact on the host Transmission of the parasite

adaptation to polymorphisms in erythrocyte receptors immune evasion parasite survival Control of parasitemia

12 Variant merozoite proteins Immune evasion Selection of merozoites by immune pressure Cooperation of antigenic variation and allelic polymorphism for immune evasion

13 Variant merozoite proteins Evasion of invasion-inhibitory antibodies Comparative inhibition assays Inhibitory Abs differentially inhibit the 2 lines. The use of alternative erythrocyte invasion pathways alters the efficacy of invasioninhibitory antibodies.

14 Variant surface antigens expressed on IEs

15 Variant surface antigens expressed on IEs Variant gene families 5 variant gene families expressed at the erythrocyte membrane PfEMP1

16 Variant surface antigens expressed on IEs PfEMP1 / The var gene family Multigene family : ~ 60 genes / haploid genome, each encoding a different PfEMP1. Subtelomeric and central var genes Chromosomal location and orientation associated with particular types of ups (5 -flanking regions) Mutually exclusive expression

17 Variant surface antigens expressed on IEs Generation of var gene repertoire diversity Molecular mechanism of allelic exclusion var gene regulation : sub-nuclear localization promoter promoter interaction Epigenetic factors chromatin remodeling Sub-nuclear localization Hot spots of recombination in malaria parasites

sub-nuclear localization promoter promoter interaction Epigenetic factors

18 Variant surface antigens expressed on IEs Generation of var gene repertoire diversity Promoter-promoter interactions

19 Variant surface antigens expressed on IEs Why exposing antigens at the surface of the host IE? rosetting sequestration clumping Immune evasion Immune dysregulation

20 Variant surface antigens expressed on IEs Sequestration and rosetting Cytoadherence of mature IEs to vascular endothelial cells in different tissues and organs sequestration avoid parasite elimination in the spleen survival severe symptoms Cytoadherence of mature IEs to uninfected erythrocytes rosette.

tissues and organs sequestration avoid parasite elimination in the spleen

21 Variant surface antigens expressed on IEs Variant-specific immunity Plasmodium falciparum Infection Elicits Both Variant-Specific and Cross-Reactive Antibodies against Variant Surface Antigens Rana Chattopadhyay and al. Infection and immunity. Feb Agglutination assays to study naturally acquired antibodies to PfEMP-1 in two areas with distinct malaria transmission patterns. Agglutination of P. falciparum field isolates with sera from children and adults residing in San Dulakudar, a village where P. falciparum malaria is hyperendemic. Sera from children lack antibodies to diverse PfEMP-1 Sera from adults recognize PfEMP-1 variants expressed by a wide range of P. falciparum isolates. frequency of agglutination

22 Variant surface antigens expressed on IEs Variant-specific immunity Mixed-agglutination assays to detect presence of cross-reactive antibodies directed against PfEMP-1 variants expressed by diverse P. falciparum isolates. e.g : serum 1C contains cross-reactive antibodies to common epitopes shared by PfEMP-1 variants expressed by P. falciparum isolate R1 and five other P. falciparum isolates (R13,R28,R30,R35,R40) Both variant-specific as well as partially cross-reactive antibodies against diverse PfEMP-1 variants develop during natural infection with P. falciparum.

23 Variant surface antigens expressed on IEs Immune evasion PfEMP1 is the major target of inhibitory Abs naturally acquired immunity requires repeated exposure to different variants of the parasite to develop variant-specific agglutinating antibodies Natural immunity to malaria is slow to develop, mainly because of the time taken to acquire antibodies to the multiple PfEMP1 variants. Age-dependent acquisition of VSA-specific antibodies Sequential expression of the PfEMP1 repertoire (antigenic variation) successive waves of parasitemia chronic infections

24 CONCLUSION Key elements for immune evasion through antigenic variation in malaria A large variant gene family Allelic exclusion Switching genes on and off at a low rate

25 Future studies How are variant proteins exported to the surface of IEs? How is signaling between the host and parasite accomplished? What is the role of the other variant multigene families?

Chapter 18: Applications of Immunology

Chapter 18: Applications of Immunology 1. Vaccinations 2. Monoclonal vs Polyclonal Ab 3. Diagnostic Immunology 1. Vaccinations What is Vaccination? A method of inducing artificial immunity by exposing