malaria morbidity and mortality continue to go unchecked in many arts of the world. As efforts mount to develop an effective vaccine, it is readily apparent that little is know regarding the immune mechanisms mediating suppression of parasitemia in the infected host. Both cell- mediated immunity (CMI) and antibody-mediated immunity (AMI) against malaria are dependent upon the activation of CD4+alphabeta T cells. The goal of this proposal is to examine the function of different T cell activating signals on the development of protective immunity against blood-stage P chabaudi malaria in the novel model of knockout (KO) mice lacking genes for the particular molecule being studied. The activating signals to be examined are cytokines activating CD4+T helper cells through the IL-2 receptor, proinflammator cytokines (IFN-gamma, IL-12 and TNFalpha), co-stimulatory molecules (CD40L and CD28) and T cell receptors (TCRalphabeta and TCRgammazeta). The parameters of immunity to be assessed are parasitemia, outcome of infection, expansion of lymphocyte subsets, expression of activation markers, production of cytokines and macrophage activation markers, production of cytokines and macrophage activation. P. Chabaudi parasitemia is suppressed by cell- mediated or antibody mechanisms of immunity thereby providing the opportunity to evaluate the function of activating signals in KO mice limited to suppressing parasitemia by either CMI or AMI. P. Chabaudi infection of KO mice provides an excellent model for studying these signals because it allows dissecting of the controlling signals that regulate the participation of AMI and CMI, both of which participate in protective immunity against both this murine malarial parasite and human P. Falciparum. The results of this proposed research will provide profiles of T cell and macrophage activation predictive of the out come of infection and reveal the cellular and molecular mechanisms of immunity that may serve as targets for immunoprophylaxis and/or immunotherapy.
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