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, Chi Zhu, Richard Ruan, Sophie F. Blanc, Trishna S. Patel, Caroline M. Worthington, Dustin R. Glasner, Bryan Castillo-Rojas, Venice Servellita, Nicholas T. N. Lo, Marcus P. Wong, Colin M. Warnes, Daniel R. Sandoval, Thomas Mandel Clausen, Yale A. Santos, Douglas M. Fox, Victoria Ortega, Anders M. Näär, Ralph S. Baric, Sarah A. Stanley, Hector C. Aguilar, Jeffrey D. Esko, Charles Y. Chiu, John E. Pak, P. Robert Beatty and Eva Harris ()
Additional contact information
Scott B. Biering: University of California, Berkeley
Francielle Tramontini Gomes de Sousa: University of California, Berkeley
Laurentia V. Tjang: University of California, Berkeley
Felix Pahmeier: University of California, Berkeley
Chi Zhu: University of California, Berkeley
Richard Ruan: University of California, Berkeley
Sophie F. Blanc: University of California, Berkeley
Trishna S. Patel: University of California, Berkeley
Caroline M. Worthington: Chan Zuckerberg Biohub
Dustin R. Glasner: University of California, San Francisco
Bryan Castillo-Rojas: University of California, Berkeley
Venice Servellita: University of California, San Francisco
Nicholas T. N. Lo: University of California, Berkeley
Marcus P. Wong: University of California, Berkeley
Colin M. Warnes: University of California, Berkeley
Daniel R. Sandoval: University of California, San Diego
Thomas Mandel Clausen: University of California, San Diego
Yale A. Santos: University of California, San Francisco
Douglas M. Fox: University of California, Berkeley
Victoria Ortega: Cornell University
Anders M. Näär: University of California, Berkeley
Ralph S. Baric: University of North Carolina at Chapel Hill
Sarah A. Stanley: University of California, Berkeley
Hector C. Aguilar: Cornell University
Jeffrey D. Esko: University of California, San Diego
Charles Y. Chiu: University of California, Berkeley
John E. Pak: Chan Zuckerberg Biohub
P. Robert Beatty: University of California, Berkeley
Eva Harris: University of California, Berkeley

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34910-5

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