MECHANISMS OF NONSTERILIZING IMMUNITY IN MALARIA

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The overall goal of our research program is to utilize the murine model of malaria to elucidate the biology of T lymphocytes activated by plasmodia, with the aim of understanding how T cells participate in protective immune responses to malaria. The proposed research will focus primarily on two important aspects of the often overlooked role of cell mediated immunity (CMI) in malaria: (i) identification and characterization CD4+ T cells that participate in protective CMI responses to acute malaria, and (ii) examination the role of gamma delta T cells as effector cells in suppressing parasite growth. To test our hypothesis that CD+4 T cells and gamma delta T cells collaborate in killing or inhibiting the growth of malarial parasites during blood-stage malaria, we will examine the role of CD4+ alphabeta T cell differentiation in the resolution of acute blood- stage P. c. adami malaria and the mechanisms of immune activation involved. This will include the study of cytokines produced by specific cell types during infection using flow cytometric and PCR techniques. Studies of antigen presentation and T cell differentiation in vivo will use the adoptive transfer of selected cells to a novel recipient, the Class II deficient A0/0 knockout mouse. The role of selected cytokines in protection and CD4+ T cell differentiation during P. c. adami malaria will be investigated by cytokine replacement in selected interleukin knockout mice. Antibody-mediated depletion and gamma delta T cell knockout mice will be used to determine whether galla delta T cells, which increase in number in both human and murine malaria, are required for the resolution of P. c. adami malaria. In addition, the identity and characteristics of gamma delta T cells responding to infection will be examined and the regulation of the gamma delta T cell subset expansion by CD4+ T cells during acute blood-stage malaria will be investigated. 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. Such information may prove vital in the design of protective vaccines and provide a basis for future cytokine therapy as has been proposed for leishmaniasis.