Stewart C Allison, Gay Carl M, Ramkumar Kavya, Cargill Kasey R, Cardnell Robert J, Nilsson Monique B, Heeke Simon, Park Elizabeth M, Kundu Samrat T, Diao Lixia, Wang Qi, Shen Li, Xi Yuanxin, Zhang Bingnan, Della Corte Carminia Maria, Fan Youhong, Kundu Kiran, Gao Boning, Avila Kimberley, Pickering Curtis R, Johnson Faye M, Zhang Jianjun, Kadara Humam, Minna John D, Gibbons Don L, Wang Jing, Heymach John V, Byers Lauren Averett
Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
bioRxiv. 2021 Jan 28:2020.05.28.122291. doi: 10.1101/2020.05.28.122291.
COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of and . We find that expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of and , resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.
新冠病毒病（COVID-19）是一种由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的传染病，该病毒通过细胞表面蛋白血管紧张素转换酶2（ACE2）和跨膜丝氨酸蛋白酶2（TMPRSS2）进入宿主细胞。我们使用来自气消化道和呼吸道的多种正常和恶性模型及组织，研究了……的表达和调控。我们发现……的表达仅限于一群高度上皮化的细胞。值得注意的是，SARS-CoV-2感染癌细胞系、支气管类器官和患者鼻上皮后，会诱导与上皮-间质转化（EMT）一致的代谢和转录变化，包括……和……的上调，导致EMT评分增加。此外，SARS-CoV-2感染会导致与紧密连接功能相关基因的转录缺失。SARS-CoV-2受体ACE2通过转化生长因子β（TGFbeta）、锌指E盒结合蛋白1（ZEB1）过表达和表皮生长因子受体（EGFR）酪氨酸激酶抑制剂耐药的发生受到EMT的抑制。这提示了一种SARS-CoV-2发病机制的新模型，即受感染细胞向间质状态转变，与急性呼吸窘迫综合征保护作用相关的紧密连接成分丧失有关。AXL抑制和ZEB1减少，如使用bemcentinib，提供了一种逆转这种效应的潜在策略。这些观察结果突出了气消化道尤其是肺癌模型系统在探索SARS-CoV-2和其他呼吸道病毒发病机制方面的作用，并为健康患者和癌症患者中COVID-19发病和死亡的潜在机制提供了重要见解。
