SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling
Scott B Biering; Francielle Tramontini Gomes de Sousa; Laurentia V. Tjang; Felix Pahmeier; Richard Ruan; Sophie F. Blanc; Trishna S. Patel; Caroline M. Worthington; Dustin R. Glasner; Bryan Castillo-Rojas; Venice Servellita; Nicholas TN Lo; Marcus P Wong; Colin M. Warnes; Daniel R. Sandoval; Thomas Mandel Clausen; Yale A. Santos; Victoria Ortega; Hector Aguilar-Carreno; Jeffrey D Esko; Charles Y Chiu; John E. Pak; P. Robert Beatty; Eva Harris.
Preprint
en Inglés
| PREPRINT-BIORXIV | ID: ppbiorxiv-472112
Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-{beta} signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-{beta} signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.
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