PROJECT SUMMARY Coccidioidomycosis, also known as Valley fever, is a fungal infection caused by inhalation of Coccidioides immitis and Coccidioides posadasii upon soil disturbance and aerosolization of the pathogen spores. Coccidioides is endemic to Southwest United States, Central America, and South America and is found in hot, dry regions. It is considered an emerging disease as it is spreading into non-endemic regions and is expected to double in endemic region this century due to global warming. Valley fever can be a fatal fungal infection that is often misdiagnosed as community acquired pneumonia and treated with several rounds of antibiotics prior to accurate diagnosis. This contributes to a growing problem of antibiotic resistance and may also alter immune responses to Coccidioides. We know that antibiotic treatment significantly shifts the lung microbiota repertoire to being less diverse, with an increase in resistant bacteria, but it is unknown how antibiotics affect the interrelationship between the host lung microbiome, the invading fungal pathogen, and the immune response. The factors contributing to the development of Valley fever as either an acute or chronic disease are unknown. Chronic infections often elicit CD4+ and CD8+ T cell exhaustion, characterized by an upregulation of inhibitory pathways and a decrease in effector function. Suppression of T cell effector function by exhaustion could promote chronic disease and serve as predictive markers of disease state. Thus, the goal of this proposal is to: 1) analyze the exhaustion state of CD4+ and CD8+ T cells in infected mice as a means of understanding the host response; and 2) determine the impact antibiotic treatment has on disease outcome. I hypothesize that CD4+ and CD8+ T cells develop an exhausted state, directly contributing to chronic fungal infection, and that an altered microbiome through antibiotic treatment negatively impacts effective fungal clearance and potentially enhances the rate of exhaustion.