Journal Article

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

Castillo-Rojas, Bryan, Stanley, Sarah A., Ruan, Richard, Servellita, Venice, Lo, Nicholas T. N., Tjang, Laurentia V., Warnes, Colin M., Näär, Anders M., Beatty, P. Robert, Ortega, Victoria, Harris, Eva, Glasner, Dustin R., Wong, Marcus P., Santos, Yale A., Pak, John E., Zhu, Chi, Fox, Douglas M., Chiu, Charles Y., Esko, Jeffrey D., Biering, Scott B., Pahmeier, Felix, Gomes de Sousa, Francielle Tramontini, Blanc, Sophie F., Baric, Ralph S., Sandoval, Daniel R., Worthington, Caroline M., Clausen, Thomas Mandel, Patel, Trishna S., Aguilar, Hector C.

2022

Overview

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 vascular leak 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 induce 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-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. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19. Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction, however, the molecular pathways resulting in endothelial barrier dysfunction and vascular leakage are only sparsely understood. Here, Biering et al. show that SARS-CoV-2 spike protein is sufficient to induce barrier dysfunction and vascular leak. They show a role for integrins, TGF-beta, ECM remodeling enzymes, and glycosaminoglycans in this S-mediated barrier dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 14/1 / 14/19 / 38 / 38/91 / 631/326/421 / 631/326/596/2557 / 631/326/596/4130 / 64 / 64/60 / 82/51 / 82/80 / 96 / 96/106 / ACE2 / Angiotensin-Converting Enzyme 2 / Coronaviruses / COVID-19 / Endothelial Cells / Extracellular matrix / Glycoproteins / Glycosaminoglycans / Humanities and Social Sciences / Humans / Inflammation / Inflammatory response / Integrins / multidisciplinary / Peptidyl-Dipeptidase A - genetics / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Signaling / Spike Glycoprotein, Coronavirus - genetics / Spike protein / Transforming Growth Factor beta / Transforming growth factor-b / Viral diseases