SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling.
| العنوان: | SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling. |
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| المؤلفون: | Biering SB; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., de Sousa FTG; 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., Ruan R; Division of Infectious Diseases and Vaccinology, School of Public Health, 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; Chan Zuckerberg Biohub, San Francisco, CA, USA., Glasner DR; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA., Castillo-Rojas B; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Servellita V; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.; 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; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Warnes CM; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Sandoval DR; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA., Clausen TM; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA., Santos YA; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA., Ortega V; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA., Aguilar HC; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA., Esko JD; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA., Chui CY; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.; Innovative Genomics Institute, University of California, Berkeley, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA., Pak JE; Chan Zuckerberg Biohub, San Francisco, CA, USA., Beatty PR; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Harris E; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.; Lead contact. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2021 Dec 13. Date of Electronic Publication: 2021 Dec 13. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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-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. |
| التعليقات: | Update in: Nat Commun. 2022 Dec 9;13(1):7630. (PMID: 36494335) |
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| معلومات مُعتمدة: | R01 AI109022 United States AI NIAID NIH HHS; R21 AI146464 United States AI NIAID NIH HHS; T32 DK007044 United States DK NIDDK NIH HHS |
| تواريخ الأحداث: | Date Created: 20211221 Latest Revision: 20240404 |
| رمز التحديث: | 20240404 |
| مُعرف محوري في PubMed: | PMC8687463 |
| DOI: | 10.1101/2021.12.10.472112 |
| PMID: | 34931188 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2021.12.10.472112 |
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