慢性肺部炎症和CK14+基底细胞增殖诱导SARS-CoV-2感染仓鼠肺泡支气管持续扩张

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-10-01 Epub Date: 2024-09-25 DOI:10.1016/j.ebiom.2024.105363
Can Li, Na Xiao, Wenchen Song, Alvin Hiu-Chung Lam, Feifei Liu, Xinrui Cui, Zhanhong Ye, Yanxia Chen, Peidi Ren, Jianpiao Cai, Andrew Chak-Yiu Lee, Honglin Chen, Zhihua Ou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Hin Chu, Anna Jin-Xia Zhang
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引用次数: 0

摘要

背景:COVID-19急性后遗症是指在感染SARS-CoV-2后很长一段时间内持续出现的一系列症状和病症,包括呼吸系统疾病。肺部组织病理学变化及其内在机制仍难以捉摸:我们研究了感染 SARS-CoV-2 的雄性仓鼠在 7、14、42、84 和 120dpi 的肺组织病理学和转录变化,并与甲型 H1N1 pdm09 感染进行了比较:我们发现,SARS-CoV-2 而非 H1N1 感染后,肺部出现病毒残留、炎症和纤维化变化。从 42dpi 到 120dpi 期间,每只感染了 SARS-CoV-2 的仓鼠(31/31)都出现了最显著的组织病理学病变,即多灶肺泡支气管化。增殖的(Ki67+)CK14+基底细胞在7dpi时聚集在支气管附近的肺泡中,它们在那里增殖并分化成SCGB1A+俱乐部细胞或Tubulin+纤毛细胞,形成肺泡-支气管化病灶。分子上,Notch通路在42和120dpi时明显上调,在肺泡-支气管化病灶中Notch3和Hes1蛋白密集表达,表明Notch信号转导参与了肺泡-支气管化的持续。空间转录组分析进一步证明了这一点。耐人寻味的是,一些促进细胞生长的通路和基因(如 Tubb4b、Stxbp4、Grb14 和 Mlf1)的显著上调与支气管化病变在空间上重叠:解读:肺部 SARS-CoV-2 感染未完全清除,病毒残留、慢性炎症和纤维化损伤以及肺泡支气管化损害了呼吸功能。在组织再生过程中,CK14+基底细胞的异常激活导致持续的 Notch 信号传导导致肺泡支气管化。这项研究加深了我们对呼吸道PASC的理解,为疾病管理提供了启示,并强调了监测呼吸道PASC患者疾病进展的必要性:经费来源见致谢部分。
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Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters.

Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.

Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.

Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.

Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.

Funding: Funding is listed in the Acknowledgements section.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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