MECHANISMS WHEREBY CD4 T CELLS ACTIVATE AMI AND CMI

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Despite many years of intensive effort to conquer malaria, it remains a leading cause of death due to an infectious disease. The recent advent of drug-resistant malarial parasites and the development of insecticide resistance by the mosquito vector jointly make the development of immune-based therapy or prophylaxis highly desirable. To do so, requires a detailed understanding of the immune response to malarial antigens. CD4+ T cells are believed to be essential for the resolution of bloodstage malaria (the stage examined in this proposal), but little is known about how CD4+ T cells actually influence protective effector mechanisms. Resolution of acute infections caused by different rodent species of Plasmodium appear to use distinct mechanisms of resolution, with P. yoelii being suppressed by antibody-mediated immunity (AMI) and P. chabaudi by cell-mediated immunity. Our goal is to use these species of Plasmodium to elucidate the molecular mechanisms whereby CD4+ T cells, by differentiating into distinct Th cell-phenotypes, regulate B cell and macrophage function during malaria. To address this goal, we intend to first examine in detail Th cell-differentiation and its requirement for resolution of infection. These findings will be incorporated into subsequent studies aimed at identifying how Th cell- differentiation affects selected parameters of protective antibody development and macrophage function during malaria. We will also address the question of whether antibodies augment macrophage function in vivo to clear parasites from blood. The results of these studies will aid in the design of future experiments crucial to our understanding of protective immune mechanisms responsible for the resolution of malaria in humans.