Abstract This Project will focus on the pathogen by undertaking transcriptomic, proteomic and genome-scale studies of Coccidioides species. Coccidioides species, C. immitis and C. posadasii, grow as a mycelium in the soil and differentiate into a unique round structure called a spherule in the mammalian host – a hallmark of their pathogenicity. Spherules enlarge and divide internally to form endospores which are released after about 4 days in the mammalian host. The mechanisms of differentiation into spherules and virulence factors of Coccidioides remain largely unknown. We are intrigued by the hypothesis that spherule-enriched genes and spherule surface- attached proteins are major players of the immune evasion strategies adopted by the pathogen. Therefore, in this Project, our overall goal is to identify genes/proteins that may play a role in (1) controlling transition from environmental-to-parasitic growth or (2) directly interacting with the host to subvert immune responses. We will take functional genomics and proteomic approaches to identify factors (i.e. transcriptional regulators) that are required for the expression of spherule-specific genes and endospore-specific genes and characterize them for their importance in spherule growth and spherule-specific gene expression profiles. In addition, we will identify fungal genes that are important for response to susceptible and resistant murine hosts, identify the secreted, surface-attached and/or GPI-anchored proteins from Coccidioides spherules, and generate knockout mutants of the candidate genes, which will be selected based on these transcriptomic and proteomics studies and our preliminary data. Mutants that show significant difference in eliciting cytokine response in cell culture will be prioritized to be tested for virulence phenotypes in mouse model of coccidioidomycosis under the activities planned in the Model Organism Core. Results of these experiments will reveal genes/proteins that are involved in regulating the parasitic growth of Coccidioides and shed light onto the molecular details of interactions between host and the pathogen.