Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection

Davalos, Oscar A.; Sebastian, Aimy; Leon, Nicole F.; Rangel, Margarita V.; Miranda, Nadia; Murugesh, Deepa K.; Phillips, Ashlee M.; Hoyer, Katrina K.; Hum, Nicholas R.; Loots, Gabriela G.; Weilhammer, Dina R.

doi:10.1128/mbio.02562-24

Title: Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection

Journal Article · 28 November 2024 · mBio (Online)

DOI: https://doi.org/10.1128/mbio.02562-24 · OSTI ID:2519310

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Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Univ. of California, Merced, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); University of California Davis Health, Sacramento, CA (United States)

Coccidioidomycosis, or Valley fever, is a lung disease caused by inhalation of Coccidioides 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 Coccidioides infection. We identified monocyte-derived Spp1-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 Coccidioides infection and suggest new therapeutic targets.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2519310

Report Number(s):: LLNL--JRNL-867863; 1103390

Journal Information:: mBio (Online), Journal Name: mBio (Online) Journal Issue: 5 Vol. 16; ISSN 2150-7511

Publisher:: American Society for Microbiology (ASM)Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Biological and medical sciences
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Valley fever
fungal pathogenesis
lung immunity
macrophages
neutrophils
scRNAseq

Title: Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection

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