Spatiotemporal analysis of lung immune dynamics in lethal <i>Coccidioides posadasii</i> infection

Coccidioidomycosis, or Valley fever, is a lung disease caused by inhalation of <i>Coccidioides</i> fungi, prevalent in the Southwestern United States, Mexico, and parts of Central and South America. Annually, the United States reports 10,000-20,000 cases, although those numbers are expected to increase as climate change expands the fungal geographic range. While 60% of infections are asymptomatic, 40% symptomatic infections are often misdiagnosed due to similarities with bronchitis or pneumonia. A small subset of infection progress to severe illness, necessitating a better understanding of immune responses during lethal infection. Using single-cell RNA sequencing and spatial transcriptomics, we characterized lung responses during <i>Coccidioides</i> infection. We identified monocyte-derived <i>Spp1</i>-expressing macrophages as potential mediators of tissue remodeling and fibrosis, marked by high expression of profibrotic and proinflammatory transcripts. These macrophages showed elevated TGF-β and IL-6 signaling, pathways involved in fibrosis pathogenesis. Additionally, we observed significant neutrophil infiltration and defective lymphocyte responses, indicating severe adaptive immunity dysregulation in lethal, acute infection. These findings enhance our understanding of <i>Coccidioides</i> infection and suggest new therapeutic targets.IMPORTANCECoccidioidomycosis, commonly known as Valley fever, is a lung disease caused by the inhalation of <i>Coccidioides</i> fungi, which is prevalent in the Southwestern United States, Mexico, and parts of Central and South America. With climate change potentially expanding the geographic range of this fungus, understanding the immune responses during severe infections is crucial. Our study used advanced techniques to analyze lung responses during <i>Coccidioides</i> infection, identifying specific immune cells that may contribute to tissue damage and fibrosis. These findings provide new insights into the disease mechanisms and suggest potential targets for therapeutic intervention, which could improve outcomes for patients suffering from severe Valley fever.