Host control in Coccidioidomycosis

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DESCRIPTION (provided by applicant): Coccidioidomycosis is a national public health problem with special intensity to Arizona, for patients with AIDS or other immunosuppression, women during pregnancy, and some ethnic minorities. It poses problems for the military and Coccidioides spp. are a potential threat to homeland security. Current therapies are inadequate. The University of Arizona has the only medical school situated within the endemic region, can support research in the biological sciences, and has an ongoing commitment improve our control of coccidioidomycosis. The unifying approach of this MRU proposal is to identify and validate Coccidioides target antigens while studying the adaptive responses of both the infecting organism and the infected host. Project 1 will improve our ability to evaluate vaccine candidates for possible clinical trials. Current assessments are highly dependent upon experimental conditions, making their interpretation ambiguous. Project 1 will use immunohistochemistry, proteomic analyses, and in situ hybridization to determine the histologic patterns of genetic and acquired resistance. We shall also examine similarities between the histological response in humans and mice. Project 2 will focus on how the fungus itself participates in the host's recovery from illness. We hypothesize that a quiescent spherule state is produced by specialized gene expression analogous to the quiescence after conidiation or other dormant saprobic structures. Gene expression will be determined from analysis of long-SAGE libraries of in vitro grown Coccidioides spp. with extension to in vivo studies of susceptible and resistant mice. Selected fungal genes associated with quiescence by these methods will be disrupted using Agrobacterioum tumefaciens-mediated transformation. Gene expression responsible for quiescence could identify novel targets for therapeutic benefit. Project 3 intends to develop an immunologic therapy for patients with widely disseminated coccidioidomycosis. Antigen-specific anergy in coccidioidomycosis can be reversed in vitro with dendritic cells (DC). To translate this advance to practical therapy, similar effects will need to be elicited by defined recombinant antigens. This project will evaluate conditions using DC as a vehicle to deliver recombinant antigens with adjuvants such as CpGs and MPL. We will also analyze the phenotype, function and cytokine profiles of lymphocyte subsets that respond to antigen-pulsed DC.