Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure

Abstract

The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria. IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.

Genome-Wide Analysis of the Malaria Parasite Plasmodium falciparum Isolates From Togo Reveals Selective Signals in Immune Selection-Related Antigen Genes

“…From these, msp1, msp7, mspdbl1, mspdbl2, ra, and sera6 were highly significantly enriched by GO analysis (P < 0.0001) ( Table 3) and have been reported previously as promising subunit candidates for a malaria multicomponent vaccine (32,39,41). Similarly, 134 genes implicated in roles for immune evasion, RBCs aggregation, or cytoadherence to microvasculature (73 rifs, 50 vars, and 12 stevors) were identified ( Supplementary Table 7), of which six rifs, seven vars, and eight stevors ( Table 3) previously as targets of acquired immunity and may serve to prevent severe malaria (42)(43)(44)(45)(46). Furthermore, the var2csa that is implicated in pregnancy placental malaria (34,47) was also observed in the top highest haplotype scores.…”

“…This analysis failed to detect selection signals for some important antigen genes such as lsa3, ama1, msp2, msp3, eba175, or circumsporozoite protein, csp [which have been entered vaccine-stage development (39,41)], and rif (PF3D7_0100400, PF3D7_0401600, or PF3D7_1254800), vars (PF3D7_1150400, PF3D7_0533100, or PF3D7_0412700), or stevors (PF3D7_1254100 or PF3D7_0300400), to mention a few (43,44,53,55), which have been identified or validated as targets of acquired immunity for vaccine development (39,42). The reason could be that iHS may not be suitable for detecting positive selection for those SNPs that have reached fixation in a local population (28).…”

Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

“…Two recent studies deliver additional data confirming the topology we deduced from our experiments. Zhou et al showed that patient-derived antibodies indeed predominantly target the predicted surface-exposed domains of STEVOR proteins (64). Andersson et al also employed N-linked glycosylation of sites within two other STEVOR variants (PF3D7_0617600 and PF3D7_1040200), revealing the same topology (65).…”

Global Repertoire of Human Antibodies Against Plasmodium falciparum RIFINs, SURFINs, and STEVORs in a Malaria Exposed Population

“…Specifically, iRBCs from patients with severe malaria were observed to often display human leucocyte immunoglobulin-like receptor B1 (LILRB1)-binding RIFINs, that contributed to the pathogenesis of the disease (2). Other studies reported RIFINs as targets of naturally acquired immunity to severe malaria (21,22). It has also been observed that increased antibody titers against certain RIFINs are associated with prompt parasite clearance and suppression of malaria symptoms in Gabonese children (23).…”