Airway Innate Immune Responses to Coccidioides Infection - Coccidioidomycosis, also known as Valley Fever, is a serious fungal infection caused by the Coccidioides species. These dimorphic fungi thrive in the arid regions of the Americas, including the southwestern United States, Mexico, and certain parts of Central and South America. Recently, there has been a substantial rise in Coccidioidomycosis cases, extending into areas previously unaffected and creating a significant health risk. Predictions suggest that by 2035, more than half of the US could be at risk. Unlike most fungal infections that typically target those with weakened immune systems, Coccidioides can also infect individuals with healthy immune systems. While many people may not show symptoms or only suffer mild, flu-like ones, serious cases can lead to ongoing lung and other organ issues, occasionally resulting in death. The reasons why the disease affects some people more severely than others remain unclear. There is an urgent need to better understand how our bodies fight off Coccidioides, especially through the initial innate immune defense. The primary route of infection involves inhaling fungal spores, leading to lung infection. Our research has discovered that a set of airway epithelial antimicrobial proteins (AMPs), including SCGB1A1 and BPIFA1, were significantly elevated in the lung without apparent inflammation or a spike in inflammatory/immune related genes. These proteins were not triggered by non-virulent fungi, hinting at a unique response to pathogenic Coccidioides. In mouse models, the absence of SCGB1A1 markedly increased susceptibility to lung fungal infection. In vitro studies have confirmed that BPIFA1, but not SCGB1A1, exhibited anti-Coccidioides activity. Furthermore, SCGB1A1 deficiency impaired airway epithelial BPIFA1 secretion by reducing extracellular vesicle production. Thus, the epithelial SCGB1A1-BPIFA1 axis plays a critical role in the early pulmonary defense against Coccidioides. Our goal is to uncover the mechanisms of early innate responses to Coccidioides infection, to understand the mechanisms of antifungal effects of BPIFA1, and to determine the mechanisms of BPIFA1 secretion regulated by SCGB1A1. This proposal represents the first effort to comprehensively investigate the molecular mechanisms and functional impact of epithelial AMPs during Coccidioides infection. Notably, all experiments involving Coccidioides spp. must be conducted within a BSL3 containment facility. Leveraging this critical resource, along with a multidisciplinary team skilled in lung epithelial biology, mycology, EV biology, and AMP engineering, we are uniquely positioned to push the boundaries of mechanistic studies and lay the foundation for the future development of innovative antifungal therapies aimed at advancing the diagnosis and treatment of Coccidioidomycosis.
