Abstract
Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or “lacunae”, in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children.
Highlights
Malaria kills hundreds of thousands of children in sub-Saharan Africa annually
The array contained 268 full-length apical membrane 1 (AMA1), the C-terminal kDa portion of merozoite surface protein 1s (MSP1-19), the entire 3D7 version of the MSP protein divided into two fragments, and 15 full-length RH5 proteins, all cloned from parasites isolated from field samples
Similar to sera from their uncomplicated malaria and healthy controls, sera from cerebral malaria (CM) cases recognized most of the AMA1, MSP1-19 and RH5 fragments (Fig. 1A)
Summary
Malaria kills hundreds of thousands of children in sub-Saharan Africa annually. Two manifestations of severe malaria - cerebral malaria and severe malarial anaemia - account for most of these deaths[1]. The var family of genes encodes one group of VSAs: P. falciparum erythrocyte membrane protein-1 (PfEMP1) antigens, large molecules expressed on the surface of the infected erythrocyte[9] that bind to endothelial receptors[10,11,12,13,14,15,16]. Expression of subsets of var genes encoding non-CD36-binding PfEMP1s has been associated with severe malarial anaemia[21,29]. The array was probed with sera from a case-control study of severe malaria in Bandiagara to test the hypothesis that low seroreactivity to specific extracellular domains of PfEMP1 field variants is associated with vulnerability to cerebral malaria or to severe malarial anaemia. Our results demonstrated that variant surface antigen lacunae predominated across case-control and acute-convalescent comparisons, with gaps in PfEMP1 seroreactivity suggestive of vulnerability to severe malaria
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