Impact of Changes in Human Airway Epithelial Cellular Composition and Differentiation on SARS-CoV-2 Infection Biology.

IF 4.7 3区 医学 Q2 IMMUNOLOGY
Journal of Innate Immunity Pub Date : 2023-01-01 Epub Date: 2023-03-25 DOI:10.1159/000530374
Melissa Thaler, Ying Wang, Anne M van der Does, Alen Faiz, Dennis K Ninaber, Natacha S Ogando, Hendrik Beckert, Christian Taube, Clarisse Salgado-Benvindo, Eric J Snijder, Peter J Bredenbeek, Pieter S Hiemstra, Martijn J van Hemert
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Abstract

The consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can range from asymptomatic to fatal disease. Variations in epithelial susceptibility to SARS-CoV-2 infection depend on the anatomical location from the proximal to distal respiratory tract. However, the cellular biology underlying these variations is not completely understood. Thus, air-liquid interface cultures of well-differentiated primary human tracheal and bronchial epithelial cells were employed to study the impact of epithelial cellular composition and differentiation on SARS-CoV-2 infection by transcriptional (RNA sequencing) and immunofluorescent analyses. Changes of cellular composition were investigated by varying time of differentiation or by using specific compounds. We found that SARS-CoV-2 primarily infected not only ciliated cells but also goblet cells and transient secretory cells. Viral replication was impacted by differences in cellular composition, which depended on culturing time and anatomical origin. A higher percentage of ciliated cells correlated with a higher viral load. However, DAPT treatment, which increased the number of ciliated cells and reduced goblet cells, decreased viral load, indicating the contribution of goblet cells to infection. Cell entry factors, especially cathepsin L and transmembrane protease serine 2, were also affected by differentiation time. In conclusion, our study demonstrates that viral replication is affected by changes in cellular composition, especially in cells related to the mucociliary system. This could explain in part the variable susceptibility to SARS-CoV-2 infection between individuals and between anatomical locations in the respiratory tract.

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人类气道上皮细胞组成和分化的变化对 SARS-CoV-2 感染生物学的影响
感染严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)会导致从无症状到致命的各种疾病。上皮细胞对 SARS-CoV-2 感染的易感性的变化取决于从呼吸道近端到远端的解剖位置。然而,这些变化背后的细胞生物学原理还不完全清楚。因此,我们采用了分化良好的原代人气管和支气管上皮细胞的气液界面培养物,通过转录(RNA 测序)和免疫荧光分析研究上皮细胞组成和分化对 SARS-CoV-2 感染的影响。通过改变分化时间或使用特定化合物研究了细胞组成的变化。我们发现,SARS-CoV-2 主要感染的不仅是纤毛细胞,还有鹅口疮细胞和瞬时分泌细胞。病毒复制受细胞组成差异的影响,这取决于培养时间和解剖来源。纤毛细胞比例越高,病毒载量越高。然而,DAPT 处理增加了纤毛细胞的数量,减少了鹅口疮细胞的数量,从而降低了病毒载量,这表明鹅口疮细胞对感染的贡献。细胞进入因子,尤其是 cathepsin L 和跨膜蛋白酶丝氨酸 2,也受到分化时间的影响。总之,我们的研究表明,病毒复制受细胞组成变化的影响,尤其是与粘膜系统有关的细胞。这在一定程度上解释了为什么不同的人和不同的呼吸道解剖位置对 SARS-CoV-2 感染的易感性不同。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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