Single-cell analysis of human airway epithelium identifies cell type-specific responses to Aspergillus and Coccidioides

Alfred T Harding, Arianne J Crossen, Jennifer L Reedy, Kyle J Basham, Olivia W Hepworth, Yangting Zhang, Viral S Shah, Hannah Brown Harding, Manalee V Surve, Patricia Simaku, Geneva N Kwaku, Kirstine Nolling Jensen, Yohana Otto, Rebecca A. Ward, George R Thompson, Bruce S Klein, Jayaraj Rajagopal, Pritha Sen, Adam L Haber, Jatin M Vyas
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Abstract

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii. To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii, providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways.
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人类气道上皮细胞的单细胞分析确定了细胞类型对曲霉菌和球孢子菌的特异性反应
呼吸道真菌感染对人类健康构成重大威胁。动物模型不能完全再现人类疾病,因此需要先进的模型来研究人类与真菌病原体之间的相互作用。在这项研究中,我们利用原代人气道上皮细胞(hAECs)在体外再现了肺部环境,并研究了细胞对两种不同的、具有临床意义的真菌病原体--曲霉菌(Aspergillus fumigatus)和球孢子菌(Coccidioides posadasii)的反应。为了了解这两种真菌的早期致病机制,我们对受感染的 hAECs 进行了单细胞 RNA 测序。分析表明,这两种真菌都能诱导细胞应激和细胞因子的产生。然而,两种真菌所影响的细胞亚型和特定通路有所不同,烟曲霉和C. posadasii分别在纤毛细胞中引发蛋白折叠相关应激,在分泌细胞中引发缺氧反应。这项研究是对感染了烟曲霉或假丝酵母菌的 hAECs 进行单细胞转录分析的首批报告之一,它提供了一个重要的数据集来剖析疾病的机制并确定潜在的靶向途径。
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