Garcia Gustavo, Wang Yijie, Ignatius Irudayam Joseph, Jeyachandran Arjit Vijey, Cario Sebastian Castillo, Sen Chandani, Li Shen, Li Yunfeng, Kumar Ashok, Nielsen-Saines Karin, French Samuel W, Shah Priya S, Morizono Kouki, Gomperts Brigitte, Deb Arjun, Ramaiah Arunachalam, Arumugaswami Vaithilingaraja
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
bioRxiv. 2022 Apr 8:2022.04.07.487520. doi: 10.1101/2022.04.07.487520.
SARS-CoV-2, responsible for the COVID-19 pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19 associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples, and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.
导致新冠疫情的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）会引发呼吸衰竭并损害多个器官系统。病毒变体的出现带来了疫苗失效和疫情持续时间延长的风险。然而，我们对SARS-CoV-2感染的分子基础以及随后的新冠病理生理学的了解有限。在这项研究中，我们发现了进化上保守的Hippo信号通路在新冠发病机制中的关键作用。鉴于新冠相关细胞损伤和免疫发病过程的复杂性，我们利用新冠肺样本以及基于多能干细胞衍生心肌细胞（PSC-CMs）和人原代肺气液界面（ALI）培养物的人类细胞模型，研究了SARS-CoV-2感染中的Hippo通路动态。SARS-CoV-2感染导致新冠肺和培养物中Hippo信号通路激活。亲本毒株和值得关注的德尔塔变体（VOC）毒株均诱导了Hippo通路。上游激酶MST1/2和LATS1的化学抑制和基因敲低导致SARS-CoV-2复制显著增强，表明其具有抗病毒作用。维替泊芬是Hippo通路下游转录激活因子YAP的药理学抑制剂，可显著降低病毒复制。这些结果阐明了Hippo信号在SARS-CoV-2感染中的直接抗病毒作用，以及该通路在药理学上作为治疗新冠靶点的潜力。
