학술논문
Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response.
Document Type
Article
Author
Garcia Jr., Gustavo; Jeyachandran, Arjit Vijey; Wang, Yijie; Irudayam, Joseph Ignatius; Cario, Sebastian Castillo; Sen, Chandani; Li, Shen; Li, Yunfeng; Kumar, Ashok; Nielsen-Saines, Karin; French, Samuel W.; Shah, Priya S.; Morizono, Kouki; Gomperts, Brigitte N.; Deb, Arjun; Ramaiah, Arunachalam; Arumugaswami, Vaithilingaraja
Source
Subject
*HIPPO signaling pathway
*SARS-CoV-2
*ETIOLOGY of diseases
*SARS-CoV-2 Delta variant
*COVID-19
*AVIAN influenza
*NEUROENDOCRINE cells
*
*
*
*
*
*
Language
ISSN
1544-9173
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (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 in vitro 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. This study shows that SARS-CoV-2 infection leads to activation of the Hippo signaling pathway in human COVID-19 lung tissue and cultured cells. The Hippo signaling pathway appears to play an antiviral role, and pharmacological inhibition of the downstream transactivator YAP reduces SARS-CoV-2 replication, with therapeutic implications. [ABSTRACT FROM AUTHOR]