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- Title
Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response.
- Authors
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
- 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.
- Subjects
HIPPO signaling pathway; SARS-CoV-2; ETIOLOGY of diseases; SARS-CoV-2 Delta variant; COVID-19; AVIAN influenza; NEUROENDOCRINE cells
- Publication
PLoS Biology, 2022, Vol 20, Issue 11, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3001851