Plasmodium falciparum antigenic variation: Relationships between in vivo selection, acquired antibody response, and disease severity

Background. Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype-VSA with a high frequency of antibody recognition (VSA_FoRH)-that is associated with young host age and severe malaria. We hypothesized that VSA_FoRH are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA_FoRH among parasites that cause malaria. Methods. We tested for associations between VSA_FoRH and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA _FoRH. Results. An expected negative association between VSA antibody repertoire and VSA_FoRH was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA_FoRH. There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA _FoRH. On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA_FoRH was observed in children with severe malaria. Conclusion. The association between the VSA_FoRH parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.