Coccidioidomycosis is a fungal respiratory disease which is endemic to desert regions of the Southwestern U.S. The most common clinical presentation is self-limited pneumonia, although the fungus is also capable of establishing systemic infections in immunocompetent individuals. The pivotal arm of host defense against coccidioidal infection is T cell mediated immunity. The T helper 1 (Th1) subset of T cells secretes cytokines that activate macrophages which contribute to protection, while Th2 cells secrete cytokines that stimulate B cells to produce antibodies which seem to provide little protection against the mycosis. A correlation exists between resistance/susceptibility to Coccidioides immitis infection and the profile of cytokine response elicited in mice. It has been shown that administration of interleukin (IL-12) to susceptible BALB/c mice either before or after intraperitoneal challenge promoted the production of interferon (IFN-gamma) and significantly reduced the fungal burden in these animals compared to controls. Evidence has also been presented that upregulation of IL-10 expression, which inhibits stimulation of the Th1 pathway of immune response, can exacerbate susceptibility to coccidioidal infection in certain strains of inbred mice. Our central hypothesis is that the virulence phenotype of C. immitis is the result of in vivo expression of multiple genes, the products of which contribute to colonization of host tissue, modulation of host immune response to the advantage of the pathogen, and maintenance of a persistent inflammatory response which can result in host tissue damage. The major goal of the proposed project is to develop a fundamental understanding of the influence of selected antigens of C. immitis upon the stimulation of innate immune cells and production of specific cytokines and chemokines that activate either a Th1 or Th2 immune response.
The specific aims of the project are focused on studies of four C. immitis gene products, three of which appear to contribute to the initiation and metastasis of the infection, and one which stimulates host protection against coccidioidal infection. We have outlined a multifaceted approach to the evaluation of the impact of these four gene products on the course of disease development. We suggest that the results of these studies will significantly advance our understanding of the pathogenesis of C. immitis.
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