A New Model for Valley Fever: Comparative Volatilomics of Coccidioides Infection

About This Grant

Project Summary: Coccidioidomycosis (Valley fever) is an emerging fungal pneumonia endemic to the southwestern United States, caused by Coccidioides immitis and C. posadasii. Unlike most fungal pathogens, these dimorphic fungi can cause severe disease in otherwise healthy individuals. The incidence of Valley fever is rising rapidly, with a 142% increase in reported U.S. cases from 2014 to 2019, and its expanding geographic range is linked to increased desertification. The economic burden exceeds $385 million annually due to delayed diagnosis and excess medical care. Despite its growing public health importance, the mechanisms driving variability in disease severity and the molecular signatures of infection remain poorly understood. Current Coccidioides infection models rely primarily on mice, which provide valuable insights but ethical and budgetary hurdles reduce the efficacy of this model. These constraints hinder the ability to investigate pathogenicity variables such as strain, dose, and life-stage transitions in a high-throughput manner. To overcome these barriers, this project proposes to develop a Galleria mellonella (greater wax moth) infection model as a scalable, ethical, and cost-effective system for studying Coccidioides infection through volatile metabolomics. Galleria have recently emerged as a promising model system for Coccidioides. Importantly, VOCs have been collected from Galleria infected with the bacterial pathogen Pseudomonas aeruginosa, establishing the technical feasibility of this proposal. Despite this potential, the Coccidioides Galleria volatilome remains unexplored. The long-term objective of this research is to establish a robust, high-throughput, and ethical infection model for Valley fever research that accelerates biomarker discovery and diagnostic development. The overall goal of this R03 proposal is to evaluate the Coccidioides Galleria infection model as a valid platform for infection-associated volatilomics. We will begin by testing our central hypothesis that Galleria infections recapitulate key volatilome characteristics observed in murine and in vitro systems, enabling its use as a comparative and translational model for Valley fever research, through one Specific Aim: 1. Compare the volatile organic compounds of the Coccidioides Galleria infection model to previously defined murine and in vitro volatilomes. Fungal burden and targeted and untargeted volatilomics will be used to characterize infection across multiple strains, enabling comparison with existing murine and in vitro models. Expected outcomes. Completion of this project will generate the first comprehensive comparison of Coccidioides volatilomes across invertebrate, mammalian, and in vitro systems. These results will have significant positive impact as it will establish the Galleria infection model as a low-cost, high-throughput, and ethically accessible tool for Coccidioides research. By facilitating discovery of breath-based biomarkers for diagnosis, prognosis, and treatment monitoring, this work directly supports the NIH mission to improve human health through innovative approaches to prevent, detect, and manage infectious diseases.