SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

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 ce...

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Bibliographic Details
Published in:bioRxiv 2021-12
Main Authors: Biering, Scott B, de Sousa, Francielle Tramontini Gomes, Tjang, Laurentia V, Pahmeier, Felix, Ruan, Richard, Blanc, Sophie F, Patel, Trishna S, Worthington, Caroline M, Glasner, Dustin R, Castillo-Rojas, Bryan, Servellita, Venice, Lo, Nicholas T N, Wong, Marcus P, Warnes, Colin M, Sandoval, Daniel R, Clausen, Thomas Mandel, Santos, Yale A, Ortega, Victoria, Aguilar, Hector C, Esko, Jeffrey D, Chui, Charles Y, Pak, John E, Beatty, P Robert, Harris, Eva
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-converting enzyme 2
Coronaviruses
COVID-19
Endothelial cells
Extracellular matrix
Glycosaminoglycans
Inflammation
Integrins
Severe acute respiratory syndrome coronavirus 2
Transcription
Transforming growth factor-b
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Summary: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 and vascular leak , independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β 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.
ISSN:2692-8205
DOI:10.1101/2021.12.10.472112