Our research program focuses on seven subject areas: (1) the nature of protection against malaria that is conferred to individuals carrying red blood cell (RBC) polymorphisms including hemoglobin C, hemoglobin S, hemoglobin E, alpha-thalassemia and G6PD deficiency; (2) the nature of infant protection against malaria in the first few months of life, involving cooperative interactions between fetal hemoglobin and maternal-derived immune antibodies; (3) the nature of naturally-acquired immunity to malaria and how it is influenced by RBC polymorphisms; (4) the molecular mechanisms by which RBC polymorphisms reduce the expression of PfEMP1, the main virulence factor of Plasmodium falciparum, on the surface of parasitized RBCs; (5) the nature of microvessel inflammation and other pathogenic processes caused by the adherence of parasitized RBCs to human microvascular endothelial cells and by the release of parasite-induced uric acid aggregates; (6) the contributions of parasite genetic and host immune factors to the clearance of P. falciparum-infected RBCs in patients treated with the antimalarial drug artesunate; and (7) the nature of the selective invasion of reticulocytes by Plasmodium vivax. In each of these areas we seek research advances that can improve the knowledge of disease processes and antimalarial drug resistance mechanisms in patients with malaria and thereby support the development of new antimalarial therapeutics and vaccines that aim to prevent illness and death. The research activities in our program are multidisciplinary and include four field studies in malarious regions of Africa and Asia as well as programs of basic laboratory investigation at NIH-sponsored laboratories in Mali and Cambodia.