Molecular and cellular analysis of host response to Cocci

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Project 2 Molecular and Cellular Analysis of Host Response to Coccidioides Project Summary In project 2, we will apply sophisticated technologies to interrogate the host response to Coccidioides. Coccidioides infections cause a broad range of disease outcomes ranging from subclinical infection to a community-acquired pneumonia, to disseminated central nervous system disease. It has been postulated that variation in the host response, including potential differences in innate and/or adaptive immune responses, contributes to the spectrum of disease manifestations. The long-term goal of Project 2 is to apply transcriptomics, mass cytometry, single-cell RNAseq, and phage display to analyze the molecular and cellular response to Coccidioides infection using both in vitro infection models and patient samples. Our goal is to examine the host response in three critical areas that benefit from the expertise and resources available to the investigators. We will establish a baseline profile of the macrophage response to Coccidioides by comparing the transcriptional profile of these host cells to infection with either wild-type or avirulent Coccidioides strains (the latter generated in the CRISPR and Virulence Core). To characterize and compare the human response to chronic infection we will use mass cytometry and single-cell RNAseq to interrogate lung nodules from Valley Fever patients in the endemic region of California. These studies would be challenging for most investigators and are made possible here by the sophisticated infrastructure available at the UCSF CoLabs (see letter of support). Additionally, we will take advantage of a rich set of clinical samples (from UC Davis, Project 3 and Clinical and Diagnostics Core) to profile cerebrospinal fluid (CSF) from patients with disseminated coccidioidal meningitis. Additionally, to determine which elements of the host response can be utilized for diagnostic applications, we will use high-resolution epitope-mapping technology to identify the most immunogenic regions of the Coccidioides proteome. Notably this project will draw new investigators into the coccidioidomycosis field. Taken together, we hope to amplify our understanding of the molecular and cellular constituents of the host response to Coccidioides infection, providing a critical foundation for the development of future diagnostics and therapeutics.