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 (VSAFoRH)-that is associated with young host age and severe malaria. We hypothesized that VSAFoRH 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 VSAFoRH among parasites that cause malaria. Methods. We tested for associations between VSAFoRH 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 VSAFoRH 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 VSAFoRH. 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 VSAFoRH was observed in children with severe malaria. Conclusion. The association between the VSAFoRH 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.
Bibliographical noteFunding Information:
Received 12 January 2005; accepted 19 April 2005; electronically published 12 August 2005. Potential conflicts of interest: none reported. Financial support: Wellcome Trust Advanced Training Fellowship in Tropical Medicine (grant 060678 to P.C.B.); Wellcome Trust Senior Fellowship (grant 631342 to K.M.); United Kingdom National Blood Service (D.J.R.). This article is published with the permission of the director of the Kenya Medical Research Institute. a Present affiliations: Wellcome Trust Sanger Institute, Cambridge, United Kingdom (A.P.); National Institute for Medical Research, London, United Kingdom (F.M.N. and S.M.K.). Reprints or correspondence: Dr. Peter C. Bull, Wellcome Trust/KEMRI Collaborative Programme, PO Box 230, Kilifi, Kenya 80108 (email@example.com).