SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein.
SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein.
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2019 冠状病毒病（COVID-19）是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2，SCV2）引起的，其发病率和死亡率高于其他呼吸道病毒感染，例如甲型流感病毒（IAV）感染。研究 SCV2 宿主感染与 IAV 的分子机制对于探索针对 SCV2 的抗病毒药物靶点至关重要。我们使用 RNA 测序评估了 SCV2 或 IAV 感染后人鼻细胞中的差异基因表达。与 IAV 相比，我们观察到代谢和细胞骨架途径的变化，表明 SCV2 感染细胞中的上皮重塑，让人想起作为对慢性损伤的反应而激活的途径。我们发现，使用 SCV2 刺突假病毒，刺突蛋白与上皮的相互作用足以引发这些上皮反应。具体来说，我们发现线粒体标记物 SIRT3 和 TOMM22 下调。此外，SCV2尖峰感染增加了细胞外酸化并降低了上皮的耗氧率。此外，我们观察到细胞骨架重排，肌动蛋白切断蛋白 cofilin-1 减少，聚合肌动蛋白增加，表明上皮细胞骨架重排。这项研究揭示了上皮细胞对 SCV2 感染的独特反应，宿主细胞中的早期线粒体功能障碍以及细胞骨架重塑的证据，这可能导致与 IAV 患者相比，COVID-19 患者的预后恶化。细胞结构和能量学的这些变化可能有助于感染早期的细胞恢复能力，从而延长细胞的存活时间，并可能为更慢性的症状铺平道路。与甲型流感相比，COVID-19 已引发全球大流行，影响了全世界数百万人，导致更高的死亡率和更持久的症状。为了研究这一点，我们比较了肺上皮对两种病毒的反应。有趣的是，我们发现，为了应对 SARS-CoV-2 感染，细胞能量发生变化，并且细胞结构发生重排。细胞结构的这些变化可能导致上皮细胞存活时间延长，即使在工作不佳的情况下，也可能导致慢性症状的发展。总之，这些发现代表了细胞在感染中存活下来的策略，但导致上皮表型发生根本性转变，具有潜在的长期后果，这可能为慢性肺病或长期 COVID-19 的发展奠定基础。
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, SCV2), which has resulted in higher morbidity and mortality rate than other respiratory viral infections, such as Influenza A virus (IAV) infection. Investigating the molecular mechanisms of SCV2-host infection vs IAV is vital in exploring antiviral drug targets against SCV2. We assessed differential gene expression in human nasal cells upon SCV2 or IAV infection using RNA sequencing. Compared to IAV, we observed alterations in both metabolic and cytoskeletal pathways suggestive of epithelial remodeling in the SCV2-infected cells, reminiscent of pathways activated as a response to chronic injury. We found that spike protein interaction with the epithelium was sufficient to instigate these epithelial responses using a SCV2 spike pseudovirus. Specifically, we found downregulation of the mitochondrial markers SIRT3 and TOMM22. Moreover, SCV2 spike infection increased extracellular acidification and decreased oxygen consumption rate in the epithelium. In addition, we observed cytoskeletal rearrangements with a reduction in the actin-severing protein cofilin-1 and an increase in polymerized actin, indicating epithelial cytoskeletal rearrangements. This study revealed distinct epithelial responses to SCV2 infection, with early mitochondrial dysfunction in the host cells and evidence of cytoskeletal remodeling that could contribute to the worsened outcome in COVID-19 patients compared to IAV patients. These changes in cell structure and energetics could contribute to cellular resilience early during infection, allowing for prolonged cell survival and potentially paving the way for more chronic symptoms. COVID-19 has caused a global pandemic affecting millions of people worldwide, resulting in a higher mortality rate and concerns of more persistent symptoms compared to influenza A. To study this, we compare lung epithelial responses to both viruses. Interestingly, we found that in response to SARS-CoV-2 infection, the cellular energetics changed and there were cell structural rearrangements. These changes in cell structure could lead to prolonged epithelial cell survival, even in the face of not working well, potentially contributing to the development of chronic symptoms. In summary, these findings represent strategies utilized by the cell to survive the infection but result in a fundamental shift in the epithelial phenotype, with potential long-term consequences, which could set the stage for the development of chronic lung disease or long COVID-19.
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DOI：
10.1152/ajplung.00050.2020
发表时间：
2020-05-01
影响因子：
4.9
作者：
Ghosh, Baishakhi;Park, Bongsoo;Sidhaye, Venkataramana K.
通讯作者：
Sidhaye, Venkataramana K.
影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
表皮生长因子受体调节丝切蛋白活性并促进传染性胃肠炎病毒进入肠上皮细胞
影响因子：
--
作者：
Hu W;Zhu L;Yang X;Lin J;Yang Q
通讯作者：
Yang Q
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
10.8
作者：
Florea, BI;Cassara, ML;Borchard, G
通讯作者：
Borchard, G