SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance.
SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance.
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DOI：
10.1038/s41467-021-24521-x
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发表时间：
2021-07-16
影响因子：
16.6
通讯作者：
Chakrabarti LA
中科院分区：
文献类型：
--
作者：
Robinot R;Hubert M;de Melo GD;Lazarini F;Bruel T;Smith N;Levallois S;Larrous F;Fernandes J;Gellenoncourt S;Rigaud S;Gorgette O;Thouvenot C;Trébeau C;Mallet A;Duménil G;Gobaa S;Etournay R;Lledo PM;Lecuit M;Bourhy H;Duffy D;Michel V;Schwartz O;Chakrabarti LA
了解 SARS-CoV-2 如何在呼吸道内传播对于定义控制 COVID-19 严重程度的参数非常重要。在这里，我们在重建的人类支气管上皮模型中检查 SARS-CoV-2 感染的功能和结构后果。尽管病毒颗粒交叉仍然有限，但 SARS-CoV-2 复制会导致上皮屏障功能短暂下降和紧密连接破坏。相反，SARS-CoV-2 复制会导致睫状层迅速丧失，其超微结构水平的特征是轴丝丧失和剩余基底体的定向错误。纤毛发生的主调节因子 Foxj1 的下调发生在纤毛大量损失之前，表明该转录因子参与了纤毛细胞的去分化。根据粘液纤毛清除试验的测量，运动纤毛功能因 SARS-CoV-2 感染而受到损害。上皮防御机制，包括基底细胞动员和干扰素-λ诱导，仅在纤毛损伤开始后才会增强。对叙利亚仓鼠 SARS-CoV-2 感染的分析进一步证明了体内活动纤毛的丧失。这项研究将纤毛损伤确定为一种致病机制，可以促进 SARS-CoV-2 传播到更深的肺实质。 SARS-CoV-2 感染会损害气道。作者在此表明，SARS-CoV-2 感染会导致气道运动纤毛迅速丧失，从而导致纤毛清除功能发生改变。在纤毛丧失之前，纤毛发生调节因子 Foxj1 的表达减少。
Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma. SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
DOI：
10.1074/jbc.ac120.013788
发表时间：
2020-10-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Felgenhauer U;Schoen A;Gad HH;Hartmann R;Schaubmar AR;Failing K;Drosten C;Weber F
通讯作者：
Weber F
DOI：
10.1016/j.cmi.2020.07.041
发表时间：
2021-01
期刊：
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
影响因子：
--
作者：
Garcia-Vidal C;Sanjuan G;Moreno-García E;Puerta-Alcalde P;Garcia-Pouton N;Chumbita M;Fernandez-Pittol M;Pitart C;Inciarte A;Bodro M;Morata L;Ambrosioni J;Grafia I;Meira F;Macaya I;Cardozo C;Casals C;Tellez A;Castro P;Marco F;García F;Mensa J;Martínez JA;Soriano A;COVID-19 Researchers Group
通讯作者：
COVID-19 Researchers Group
影响因子：
56.9
作者：
Lamers, Mart M.;Beumer, Joep;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
56.9
作者：
Broggi, Achille;Ghosh, Sreya;Zanoni, Ivan
通讯作者：
Zanoni, Ivan