Virulence gene discovery in Coccidioides

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Project 1 Summary: Virulence Gene Discovery in Coccidioides The focus of Project 1 is virulence gene discovery in Coccidioides. Despite the impact of Coccidioides infection, the molecular understanding of virulence mechanisms in this fungus is limited. Only a handful of Coccidioides genes have been implicated any virulence-relevant traits. Given the need to accelerate drug discovery and resolve the public health crisis posed by this fungus in the endemic areas, it is imperative to dissect virulence strategies used by Coccidioides to manipulate the host. Here we apply powerful systems-level tools to identify virulence-relevant genes. Such a landmark discovery effort will help open up the field at long last, providing a rich source of virulence genes to serve as new therapeutic targets. The ability of Coccidioides to cause disease depends on an elaborate developmental transition from saprophytic soil form to host form. Specifically, the hyphal form of the organism produces arthroconidia, which disperse easily and can be inhaled by mammalian hosts. Once inside the host lung, arthroconidia germinate, enlarge, and undergo nuclear division and segmentation to form large spherules filled with vegetative endospores. Rupture of the spherules allows release of endospores and dissemination of the fungus to other sites. Here we bring together a powerful team of scientists with expertise in the basic biology of thermally dimorphic fungi and statistical genetics, and in successful application of drug screens to target the growth and development of microbial pathogens, including fungi. Given the critical role of spherule development in disease progression, a major focus of this project is the genomic and genetic dissection of this process. We will identify candidate genes that govern spherulation by taking advantage of three complementary approaches: (1) Genome-wide association studies (GWAS); (2) high-resolution transcriptomics and proteomics of spherulation; and (3) drug repurposing to identify chemicals that inhibit spherulation and/or fungal growth. Taken together, these approaches will allow us to elucidate critical molecular events that take place during spherule development in the context of infection as well as identify new candidate therapeutics.