Immune and metabolic correlates of Coccidioides disease spectrum and outcomes

Coccidioides infection leads to acute or chronic pulmonary disease (Valley Fever) with a wide spectrum of disease severity. However, the mechanisms of coccidioidomycosis severity and therapeutic failures are not fully elucidated and correlates of disseminated or unresolved infection are not well established. The overall objective of Project 3 is to investigate the immune and metabolic correlates of Coccidioides infection and disease spectrum and to identify mechanisms of disease pathogenesis. Our preliminary data of immune responses and metabolomic profiles in samples from patients infected with Coccidioides identified the metabolic signature of key dysregulated pathways. We hypothesize that Coccidioides infection-induced metabolic changes reflecting the major dysregulated host cellular pathways can predict disease severity and clinical outcomes. We propose to build on our collective strengths in coccidioidomycosis diagnostics and clinical care of large patient cohorts with Coccidioides infection at UC Davis to determine the pathogenic mechanisms of coccidioidomycosis and to investigate a prognostic biosignature that can identify the future course of disease progression. This project leverages the availability of clinical sample collection from patients with coccidioidomycosis and database, resources from the existing Centers, technical and scientific knowledge of immunological and metabolic analyses, mouse models of coccidioidomycosis, strong preliminary data and a multi-disciplinary research team. There are three specific aims. Aim 1: To determine immune and metabolic correlates of the disease spectrum and infection outcomes and identify pathways for therapeutic targeting. Longitudinal samples from newly diagnosed patients with Coccidioides at UC Davis will be evaluated for immune and metabolic changes and the key dysregulated cellular/metabolic pathways and correlates of disease outcomes will be identified. Aim 2: To identify immune and metabolic correlates of treatment failures and determine mechanisms contributing to this treatment failure. Disseminated Coccidioides infection with severe disease is associated with morbidity/mortality. Clinical samples from patients with disseminated Coccidioides receiving clinical care at UC Davis will be enrolled in this prospective study. Aim 3: To investigate the pathogenic determinants of Coccidioides that promote induction of immune and metabolic dysfunction and lung pathology in vivo. We will utilize the mouse model of coccidioidomycosis to investigate the development of lung pathology, eosinophilia and metabolic dysregulation by Coccidioides wild-type and mutant strains and map the pathogenic determinants. An integrated analysis will be performed of host responses to Coccidioides in vivo through clinical (Project 3), metabolic (Project 3) and transcriptomic (Project 2) data and to Coccidioides mutant strains in vitro and in the mouse model (Core 3, Projects 1 and 2) Collectively, our proposed studies will (a) fill the gaps in our understanding of the role of both pathogenic determinants and host factors contributing to the disease spectrum of Valley Fever and (b) identify potential correlates of disease outcomes and targets for therapy.