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SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-ß signaling.
Biering, Scott B; Gomes de Sousa, Francielle Tramontini; Tjang, Laurentia V; Pahmeier, Felix; Zhu, Chi; 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; Fox, Douglas M; Ortega, Victoria; Näär, Anders M; Baric, Ralph S; Stanley, Sarah A; Aguilar, Hector C; Esko, Jeffrey D; Chiu, Charles Y; Pak, John E; Beatty, P Robert; Harris, Eva.
  • Biering SB; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. sbiering@berkeley.edu.
  • Gomes de Sousa FT; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Tjang LV; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Pahmeier F; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Zhu C; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Ruan R; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • Blanc SF; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Patel TS; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Worthington CM; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Glasner DR; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • Castillo-Rojas B; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Servellita V; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
  • Lo NTN; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Wong MP; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Warnes CM; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
  • Sandoval DR; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Clausen TM; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Santos YA; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Fox DM; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
  • Ortega V; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
  • Näär AM; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Baric RS; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
  • Stanley SA; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
  • Aguilar HC; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Esko JD; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
  • Chiu CY; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Pak JE; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • Beatty PR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Harris E; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Nat Commun ; 13(1): 7630, 2022 Dec 09.
Article in English | MEDLINE | ID: covidwho-2160206
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-ß signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-ß 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-34910-5

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-34910-5