Early in vivo expressed antigens and their role in virulence, immune response, and vaccines for coccidioidomycosis

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Project Summary/Abstract (Animal Core) Coccidioides immitis and C. posadasii cause coccidioidomycosis (Valley Fever - VF), which is of great concern due to recent rapid increases in US disease incidence. The overall goal of our program (VIRV-CCRC) is to in- vestigate proteins that are highly expressed early in the VF infection cycle, when the fungal arthroconidia are developing into spherules and endospores forming. Our hypothesis in Research Project 1 (RP1) is that pro- teins expressed at this critical stage are key to disease progression and potential represent virulence factors. The Animal Core (AnC) will be instrumental in addressing this hypothesis by providing new animal models for virulence testing. In Aim 1, the Galleria (wax worm) invertebrate model that we have shown supports arthro- conidia development into mature spherules represents a good test of virulence factors key to this step. It is also economical and will reduce the number of mice needed for research. Nevertheless, the mouse model pro- vides data that Galleria cannot and the AnC will provide it to confirm Galleria virulence data. In aim 2, mouse challenge experiments will be conducted at the ABSL3 facility at Northern Arizona University. Identification of early infection virulence factors will be used guide the identification of T cell epitopes in a T cell receptor analy- sis in RP2. T cell recognition of Coccidioides epitopes is a key step in the immune response, which we will lev- eraged into novel VF diagnostic tests. Both virulence factor and T cell receptor results will guide the prioritiza- tion of advanced nucleic acid (RNA and DNA) vaccine development. RP3 will use the mouse model and a non- human primate model to develop and test new vaccines. In aim 3, we will develop a new pig-tailed macaque (NHP) model. Our focus on this model is due to their established VF susceptibility and the availability of natu- rally infected colony animals from the Arizona Breed Colony (WaNPRC). The AZ macaque disease incidence is similar to the Arizona human population and represents a valuable source of pathology data, serum, PBMC, and other tissues. The Fuller lab (RP3) has already successfully used pig-tailed macaques in vaccination stud- ies, achieving high antibody titers and protective immunity to other diseases. The AnC will coordinate the vac- cine work through the naturally infected NHP population in Arizona, the Seattle WaNPRC facility for NHP im- munization studies, and at Tulane National Primate Research Center for Coccidioides challenge studies in NHP. In summary, the AnC will develop, provide, and support three complementary animal models: Galleria, mouse, and NHP. Each has its distinct advantages that support the individual and overall research goals of the VIRV-CCRC. The AnC is a coordinated effort across three institutions and four locations that leverages institu- tional strengths to maximize productive of the whole VIRV-CCRC. As the VIRV-CCRC develops these animal model resources, we will encourage collaboration with other CCRC and broadly with the Valley Fever research community. High quality animal models and their tissue specimens will alleviate some of the research barriers to developing better therapeutic agents, diagnostic tests, and preventive vaccines.