Early immune response to Coccidioides is characterized by robust neutrophil and fibrotic macrophage recruitment and differentiation

Abstract

Coccidioidomycosis, or Valley fever, is an emerging respiratory disease caused by soil dwelling fungi of the Coccidioides 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 under defined. Here, we probed the early immune response to Coccidioides using a high dose of an attenuated strain of C. posadasii in 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 to Coccidioides and provide a deeper understanding of host-pathogen interactions in the lung. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/609001v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@198a77forg.highwire.dtl.DTLVardef@11c9207org.highwire.dtl.DTLVardef@b71257org.highwire.dtl.DTLVardef@115447d_HPS_FORMAT_FIGEXP M_FIG C_FIG 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 Coccidioides 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 Coccidioides infection, offering valuable directions for developing more effective treatments and preventive strategies against this increasingly prevalent disease.