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
Physical and Life Sciences Directorate, Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, USA.
Department of Molecular and Cell Biology, School of Natural Sciences, Health Sciences Research Institute, University of California Merced, Merced, California, USA.
mBio. 2025 May 14;16(5):e0256224. doi: 10.1128/mbio.02562-24. Epub 2024 Nov 29.
Coccidioidomycosis, or Valley fever, is a lung disease caused by inhalation of 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 infection. We identified monocyte-derived -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 infection and suggest new therapeutic targets.IMPORTANCECoccidioidomycosis, commonly known as Valley fever, is a lung disease caused by the inhalation of 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 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.
球孢子菌病，又称山谷热，是一种因吸入真菌而引起的肺部疾病，在美国西南部、墨西哥以及中美洲和南美洲部分地区较为流行。美国每年报告10000 - 20000例病例，不过随着气候变化扩大真菌的地理分布范围，预计这些数字将会增加。虽然60%的感染是无症状的，但40%有症状的感染常常因与支气管炎或肺炎相似而被误诊。一小部分感染会发展为严重疾病，因此有必要更好地了解致死性感染期间的免疫反应。我们使用单细胞RNA测序和空间转录组学技术，对感染期间的肺部反应进行了表征。我们确定单核细胞衍生的表达巨噬细胞是组织重塑和纤维化的潜在介质，其特征是促纤维化和促炎转录本的高表达。这些巨噬细胞显示出TGF-β和IL-6信号通路升高，这些通路参与纤维化发病机制。此外，我们观察到显著的中性粒细胞浸润和淋巴细胞反应缺陷，表明在致死性急性感染中存在严重的适应性免疫失调。这些发现加深了我们对感染的理解，并提出了新的治疗靶点。重要性球孢子菌病，通常称为山谷热，是一种因吸入真菌而引起的肺部疾病，在美国西南部、墨西哥以及中美洲和南美洲部分地区较为流行。随着气候变化可能扩大这种真菌的地理范围，了解严重感染期间的免疫反应至关重要。我们的研究使用先进技术分析感染期间的肺部反应，确定了可能导致组织损伤和纤维化的特定免疫细胞。这些发现为疾病机制提供了新见解，并提出了治疗干预的潜在靶点，这可能改善严重山谷热患者的治疗结果。
