Early immune response to <i>Coccidioides</i> is characterized by robust neutrophil and fibrotic macrophage recruitment and differentiation

Coccidioidomycosis, or Valley fever, is an emerging respiratory disease caused by soil-dwelling fungi of the <i>Coccidioides</i> genus that is expected to spread from the southwest into the central U.S. by 2050. While 60% of infections are asymptomatic, the other 40% of patients experience a range of symptoms, from self-limiting pneumonia to life-threatening disseminated disease. The immunological events that underlie the progression to severe disease remain underdefined. Here, we probed the early immune response to <i>Coccidioides</i> using a high dose of an attenuated strain of <i>Coccidioides posadasii</i> in a mouse model of infection coupled with single-cell RNA sequencing. At 24 h post-infection, robust immune infiltration is detected in the lung, marked by high levels of inflammatory PD-L1⁺ neutrophils and fungal-contact-dependent pro-fibrotic Spp1⁺ macrophages. These findings elucidate the early dynamics of the host response to <i>Coccidioides</i> and provide a deeper understanding of host-pathogen interactions in the lung.IMPORTANCEBy examining early immune dynamics in the lungs, we uncover critical insights into how myeloid cells, particularly neutrophils and macrophages, are recruited and differentiated during <i>Coccidioides</i> infection. The discovery of specific immune cell subsets, such as PD-L1⁺ neutrophils and Spp1⁺ macrophages, which are associated with inflammation and fibrosis, highlights potential targets for therapeutic intervention. These findings provide a deeper understanding of the host-pathogen interactions that occur during <i>Coccidioides</i> infection, offering valuable directions for developing more effective treatments and preventive strategies against this increasingly prevalent disease.