Genetic Diversity of Plasmodium falciparum and Severe Malaria in Africa

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DESCRIPTION (provided by applicant): Malaria continues to have a major impact on global health with rates of 1-3 million deaths annually, the vast majority of which occur in children in sub-Saharan Africa as a result of severe malaria (i.e., severe malaria anemia and cerebral malaria). The clinical syndrome of cerebral malaria, thus far definitively diagnosed only by autopsy, probably results from the complex interactions of the human host, the infecting parasite, and the environmental dynamics of transmission. The unique ability of Plasmodium falciparum to adhere to the endothelium of the human host and thus sequester itself from the circulation has clearly been shown to be necessary but not sufficient to account for mortality. Elucidation of the role of parasite genetic diversity in the pathology of cerebral malaria could lead to powerful drug targets, expand the spectrum of vaccine formulations, and define previously unknown mechanisms of pathogenesis. The recent availability of extremely powerful Plasmodium falciparum genome wide screens for genetic polymorphisms which utilize small amounts of parasite DNA allow for very detailed study of questions the variable pathologic lesions seen in cerebral disease. The long term goal of this proposal is 1) to fully define the concept of Plasmodium falciparum genetic diversity as it contributes to severe disease and 2) to provide the investigator with the additional necessary complementary skills of genomics research and epidemiological methods to develop into an independent investigator in malaria.