Airway innate immune responses to coccidioides infection - coccidioidomycosis, also known as valley fever, is a serious fungal infection caused by the coccidioides species

The National Institute of Allergy and Infectious Diseases (NIAID) awarded the University of Arizona a Project Grant of $3,075,549 under the Allergy and Infectious Diseases Research program (CFDA 93.855) on July 28, 2025, with a completion date of June 30, 2029. This research initiative investigates airway innate immune responses to Coccidioides infection, a serious fungal disease commonly known as valley fever that is expanding geographically across the United States. The research focuses on understanding how the body's initial immune defenses combat Coccidioides infection through the airways, with particular emphasis on airway epithelial antimicrobial proteins (AMPs), specifically SCGB1A1 and BPIFA1. The study builds on preliminary findings demonstrating that these proteins are elevated in lung tissue in response to pathogenic Coccidioides, that SCGB1A1 deficiency increases susceptibility to lung fungal infection in mouse models, and that BPIFA1 exhibits direct anti-Coccidioides activity.

The project incorporates collaboration through a federal grant sub-award to Massachusetts General Hospital (awarded November 4, 2025), which will contribute its research expertise through the institution's Research Management Division. The research products and services delivered through this award will include fundamental scientific knowledge regarding the SCGB1A1-BPIFA1 axis in early pulmonary defense against Coccidioides, experimental findings from in vitro and animal model studies, and potentially translational insights applicable to understanding variable disease severity across infected populations. The award addresses an urgent public health need, as current epidemiological projections indicate that more than half of the United States could be at risk for coccidioidomycosis by 2035.

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.