Extension to A record- funds for sequencing: Measuring the impact of naturally acquired immunity on the expression of Plasmodium falciparum variant surface antigens. (360G-Wellcome-084535_Z_07_B)

Plasmodium falciparum infected erythrocytes express on their surface, members of a diverse family of parasite molecules called PfEMP1 that are encoded by a family of 60 var genes. These molecules interact with the surface of host cells and mediate parasite sequestration in tissues including the brain, an important step in the pathogenesis of cerebral malaria. Although naturally acquired antibodies to PfEMP1 provide specific protection against the molecular variants that they recognise, PfEMP1 ar e often considered too diverse to be vaccine candidates. However, we and others have shown that parasites infecting children with severe malaria tend to express serotypes that are more broadly recognised suggesting they may be antigenically restricted. Studies of a laboratory isolate suggest that the most broadly recognised PfEMP1 types are encoded by a genetically distinct subset of groupA var genes. By sequencing short var sequence tags expressed in parasites from Kenya, we have shown that expression of sequences with groupA-like features are associated with younger children and that a smaller subset of these sequences are associated with severe malaria. We propose to identify new targets of malaria intervention by characterizing these specific subsets of PfEMP1 that are associated with infections of children with low natural immunity.