Mechanisms of Nonsterilizing Immunity in Malaria

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DESCRIPTION (provided by applicant): The ability to protect human subjects against Plasmodium falciparum blood-stage malaria by immunization or immunotherapy requires an understanding of anti-malarial immune responses beyond what is currently known. While there is a remarkable redundancy in various immune pathways that control blood-stage malaria, IFNgamma production appears to be the single factor that consistently influences antibody-mediated (AMI) and cell-mediated (CMI) resistance to blood-stage parasites. From extensive studies of IFNgamma and its role in the development and regulation of innate and acquired immune responses against diverse pathogens, it is clear that there are multiple pathways, cell populations and effectors functions under the influence of IFNgamma. However, we do not fully understand the exact role of IFNy in the control of blood-stage malaria by innate immune responses, or by acquired cell-mediated immune responses, by acquired antibody-mediated immune responses. Likewise, we do not fully understand the interdependence of these IFNv-driven responses on the ultimate ability of the host to suppress the growth of blood-stage malaria parasites. The overall hypothesis for our proposed study is that IFNgamma 1) is essential early in the initiation of the innate immune response leading to both AMI and CMI, 2) is necessary for the expression of CMI during the effector phase of the adaptive immune response and 3) enhances the suppression of parasitemia by antibody-mediated effector mechanisms. We will address this hypothesis experimentally by studying specific populations of immune cells throughout the course of acute P. chabaudi malaria. Specifically, we will focus on 1) establishing the kinetics of IFNgamma production, 2) identifying the critical populations of cells producing IFNgamma and responding to IFNgamma and 3) linking IFNgamma dependent immune effector mechanisms to the resolution of infection. In using the P. chabaudi murine model and selected immunologic knockout mice, we have the unique ability to establish the distinct IFNgamma dependent pathways that lead to cell-mediated immunity or to antibody-mediated immunity during malaria. As important, we will identify critical IFNgamma dependent responses required for both arms of the protective response. We firmly believe that these studies will significantly extend our knowledge on the mechanisms by which IFNy drives antimalarial immune responses and identify IFNgamma-dependent components of anti-malaria immunity that can and should be targeted by immunization.