T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

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PROJECT SUMMARY/ABSTRACT Disseminated coccidioidomycosis (DCM) is an uncommon but life-threatening consequence of infection by the fungus Coccidioides. Why some people get DCM and others a mild pulmonary disease (“Valley Fever”), or remain asymptomatic is unknown. There are no effective treatments for DCM, and patients who survive must remain on antifungals for life. Thus, there is an urgent need for a better understanding of DCM and for better treatments. Based on decades of work by human and mouse immunologists, we believe the host's immune responses to Coccidioides are defective in DCM and center on a failure of interferon-gamma (IFN-ɣ) production by helper T cells (an immunogenetic program called Type-1 immunity). The importance of Type-1 immunity in the immune response to Coccidioides is further evidenced by a patient we have described with DCM, hypomorphic function of the IL-12 receptor, and a severe defect in Th1 differentiation. We showed in this case that DCM could be cleared after innovative treatment with IFN-ɣ and a clinically-available blocking antibody of IL-4 receptor. Together, our preliminary and published data support the central hypothesis that Th cell dysfunction provokes the development of DCM in a significant fraction of patients. If proven out, screening for Th dysfunction and treatment with IFN-γ and IL-4 receptor blockade could rescue these genetic perturbations and offer a treatment for DCM. To study the immune response in DCM, we have assembled a team of immunologists, geneticists, and infection experts from UCLA, and have partnered with the Valley Fever Institute (VFI), the largest Coccidioides clinic in California, to provide samples from DCM and uncomplicated Valley Fever (UVF). Our Aims include 1) Identify type-2 skewed individuals with DCM and their genetic underpinnings; and 2) Discover transcriptional patterns and pathways of immune dysfunction in DCM. The overall impact of this work is to accelerate the search for highly effective treatments for this life- threatening fungal infection. Our work will also establish a genetic basis for predicting susceptibility to DCM that can be tested in future work. Additionally, we will demonstrate in vitro the ability of two FDA-approved drugs to skew memory T cell responses against Coccidioides, representing the first steps towards a clinical trial and the establishment of a new treatment for an otherwise incurable disease.