Early immune response toCoccidioidesis characterized by robust neutrophil and fibrotic macrophage recruitment and differentiation

Abstract

AbstractCoccidioidomycosis, or Valley fever, is an emerging respiratory disease caused by soil dwelling fungi of theCoccidioidesgenus 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 under defined. Here, we probed the early immune response toCoccidioidesusing a high dose of an attenuated strain ofC. posadasiiin a mouse model of infection coupled with single-cell RNA sequencing. At 24 hours 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 toCoccidioidesand 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 duringCoccidioidesinfection. 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 duringCoccidioidesinfection, offering valuable directions for developing more effective treatments and preventive strategies against this increasingly prevalent disease.