PLoS Biol . Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response

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PLoS Biol


. 2022 Nov 8;20(11):e3001851.
doi: 10.1371/journal.pbio.3001851. eCollection 2022 Nov.
Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response


Gustavo Garcia Jr ¹ , Arjit Vijey Jeyachandran ¹ , Yijie Wang ² , Joseph Ignatius Irudayam ¹ , Sebastian Castillo Cario ¹ , Chandani Sen ³ , Shen Li ² , Yunfeng Li ⁴ , Ashok Kumar ⁵ , Karin Nielsen-Saines ³ , Samuel W French ⁶ , Priya S Shah ⁷ , Kouki Morizono ^{8 9} , Brigitte N Gomperts ^{3 6 10 11} , Arjun Deb ^{2 10 11 12 13} , Arunachalam Ramaiah ^{14 15 16} , Vaithilingaraja Arumugaswami ^{1 10 12}



Affiliations

• PMID: 36346780
• DOI: 10.1371/journal.pbio.3001851

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.