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Infection and Immunity, October 2006, p. 5955-5963, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00481-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Duffy Binding-Like Domains That Bind Chondroitin Sulfate A and Protection against Pregnancy-Associated Malaria

Malaria Group, International Centre for Genetic Engineering, and Biotechnology (ICGEB), New Delhi 110067, India,¹ Unité de Parasitologie Expérimentale, Faculté de Médecine, Université de la Méditerranée, Marseille, France²

Received 24 March 2006/ Returned for modification 4 June 2006/ Accepted 3 July 2006

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). P. falciparum isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placental P. falciparum isolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded by var genes, that bind CSA. Immunization of mice with the CSA-binding DBL3 domain encoded by var1CSA elicits cross-reactive antibodies that recognize diverse CSA-binding P. falciparum isolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily express var2CSA, which does not encode any DBL domains. Here, we demonstrate that antibodies raised against DBL3 encoded by var1CSA cross-react with one of the CSA-binding domains, DBL3X, encoded by var2CSA. This explains the paradoxical observation made here and earlier that anti-rDBL3 sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM.

Editor: J. L. Flynn