tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Arjit Vijey Jeyachandran[SUP] 1 [/SUP], Yijie Wang[SUP] 2 [/SUP], Joseph Ignatius Irudayam[SUP] 1 [/SUP], Sebastian Castillo Cario[SUP] 1 [/SUP], Chandani Sen[SUP] 3 [/SUP], Shen Li[SUP] 2 [/SUP], Yunfeng Li[SUP] 4 [/SUP], Ashok Kumar[SUP] 5 [/SUP], Karin Nielsen-Saines[SUP] 3 [/SUP], Samuel W French[SUP] 6 [/SUP], Priya S Shah[SUP] 7 [/SUP], Kouki Morizono[SUP] 8 9 [/SUP], Brigitte N Gomperts[SUP] 3 6 10 11 [/SUP], Arjun Deb[SUP] 2 10 11 12 13 [/SUP], Arunachalam Ramaiah[SUP] 14 15 16 [/SUP], Vaithilingaraja Arumugaswami[SUP] 1 10 12 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Arjit Vijey Jeyachandran[SUP] 1 [/SUP], Yijie Wang[SUP] 2 [/SUP], Joseph Ignatius Irudayam[SUP] 1 [/SUP], Sebastian Castillo Cario[SUP] 1 [/SUP], Chandani Sen[SUP] 3 [/SUP], Shen Li[SUP] 2 [/SUP], Yunfeng Li[SUP] 4 [/SUP], Ashok Kumar[SUP] 5 [/SUP], Karin Nielsen-Saines[SUP] 3 [/SUP], Samuel W French[SUP] 6 [/SUP], Priya S Shah[SUP] 7 [/SUP], Kouki Morizono[SUP] 8 9 [/SUP], Brigitte N Gomperts[SUP] 3 6 10 11 [/SUP], Arjun Deb[SUP] 2 10 11 12 13 [/SUP], Arunachalam Ramaiah[SUP] 14 15 16 [/SUP], Vaithilingaraja Arumugaswami[SUP] 1 10 12 [/SUP]
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.