: This proposal examines the regulatory effects of parasite- and host-derived activation factors on the macrophage response in experimental African trypanosomiasis. African trypanosomes cause a fatal disease of man and animals that is characterized by extensive functional, histological and pathological changes in the lymphoid tissues of infected hosts. Among these changes is an increase in the numbers and activation state of cells of the mononuclear phagocyte system. Macrophage activation during infection appears to occur in response to glycosyiphosphatidylinositol residues of the variant surface glycoprotein membrane anchor as well as to IFN-gamma produced by T cells in response to parasite antigens. There is evidence that these two factors produce distinct patterns of macrophage activation during infection, and that the balance or interaction of the different activation signals may determine the progression of disease and outcome of infection. Since the macrophage activation response is based on distinct membrane-associated signaling events, and since macrophage activation is intimately linked to host protection, an effort to understand the molecular basis for macrophage activation is clearly an important scientific step towards understanding the host-parasite relationship. Therefore, this proposal examines basic elements of cell biology and molecular signaling to dissect the macrophage activation response in African trypanosomiasis. The ultimate goal is to uncover novel regulatory mechanisms associated with macrophage activation that can be exploited to provide greater resistance to disease.
