Leishmania amazonensis is associated with localized cutaneous, diffuse cutaneous, and visceral leishmaniasis in humans. Most inbred strains of mice are susceptible to this New World parasite; however, the mechanism for this generalized susceptibility is poorly defined. There is evidence that susceptibility of mice to this parasite is not due to an enhanced T helper (Th)2 response. Recent studies of gene knockout mice suggest a correlation between the activation of Th1-like cells and the pathogenesis. These findings are distinct from previous studies of murine L. major infection and have suggested a novel mechanism operating on susceptibility of the host to L. amazonensis. We propose that the pathogenesis of L. amazonensis infection is the consequence of an inappropriate induction and activation of Th1-type responses. The major goal of this application is to define the mechanisms of inflammatory responses to and pathogenesis of L. amazonensis infection. Specifically the experimental approaches are: (1) to examine the role of CD4+ T cells in pathogenesis of L. amazonensis and L. major infections in mice of different genetic backgrounds and to determine if pathological changes in these mice are mediated by a similar or a distinct mechanism; (2) to define the nature and characteristics of CD4+ T cells in vaccine-induced resistant mice and in susceptible mice following infection with L. amazonensis and the mechanism of action of CD4+ T cells in protective immunity and in pathogenesis; (3) to seek potential interventions for the control of infection and pathology. The functional roles of Th1 cytokines and adhesion molecules in the regulation of immune and inflammatory responses will be examined using recombinant cytokines and gene knockout mice. This proposal represents a distinct area of investigation and should provide better understanding of complex mechanisms associated with adverse clinical manifestations of cutaneous leishmaniasis.
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