SARS-CoV-2 Spike Triggers Barrier Dysfunction and Vascular Leak Via Integrins and TGF-β Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Dec 9

PMID 36494335

Authors

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 Naar

Ralph S Baric

Sarah A Stanley

Hector C Aguilar

Jeffrey D Esko

Charles Y Chiu

John E Pak

P Robert Beatty

Eva Harris

Affiliations

Soon will be listed here.

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.

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References

Hartenian E, Nandakumar D, Lari A, Ly M, Tucker J, Glaunsinger B . The molecular virology of coronaviruses. J Biol Chem. 2020; 295(37):12910-12934. PMC: 7489918. DOI: 10.1074/jbc.REV120.013930. View

Biering S, Van Dis E, Wehri E, Yamashiro L, Nguyenla X, Dugast-Darzacq C . Screening a Library of FDA-Approved and Bioactive Compounds for Antiviral Activity against SARS-CoV-2. ACS Infect Dis. 2021; 7(8):2337-2351. DOI: 10.1021/acsinfecdis.1c00017. View

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S . SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2):271-280.e8. PMC: 7102627. DOI: 10.1016/j.cell.2020.02.052. View

Beddingfield B, Iwanaga N, Chapagain P, Zheng W, Roy C, Hu T . The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection. JACC Basic Transl Sci. 2020; 6(1):1-8. PMC: 7566794. DOI: 10.1016/j.jacbts.2020.10.003. View

Ruoslahti E . RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996; 12:697-715. DOI: 10.1146/annurev.cellbio.12.1.697. View

Ferreira-Gomes M, Kruglov A, Durek P, Heinrich F, Tizian C, Heinz G . SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun. 2021; 12(1):1961. PMC: 8010106. DOI: 10.1038/s41467-021-22210-3. View

Raghavan S, Kenchappa D, Leo M . SARS-CoV-2 Spike Protein Induces Degradation of Junctional Proteins That Maintain Endothelial Barrier Integrity. Front Cardiovasc Med. 2021; 8:687783. PMC: 8225996. DOI: 10.3389/fcvm.2021.687783. View

Zhang Q, Chen C, Swaroop M, Xu M, Wang L, Lee J . Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro. Cell Discov. 2020; 6(1):80. PMC: 7610239. DOI: 10.1038/s41421-020-00222-5. View

Zhang L, Jackson C, Mou H, Ojha A, Peng H, Quinlan B . SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat Commun. 2020; 11(1):6013. PMC: 7693302. DOI: 10.1038/s41467-020-19808-4. View

10.

Kamiyama S, Suda T, Ueda R, Suzuki M, Okubo R, Kikuchi N . Molecular cloning and identification of 3'-phosphoadenosine 5'-phosphosulfate transporter. J Biol Chem. 2003; 278(28):25958-63. DOI: 10.1074/jbc.M302439200. View

11.

Bonaventura A, Vecchie A, Dagna L, Martinod K, Dixon D, Van Tassell B . Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol. 2021; 21(5):319-329. PMC: 8023349. DOI: 10.1038/s41577-021-00536-9. View

12.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

13.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-422. PMC: 7164771. DOI: 10.1016/S2213-2600(20)30076-X. View

14.

Leist S, Dinnon 3rd K, Schafer A, Tse L, Okuda K, Hou Y . A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice. Cell. 2020; 183(4):1070-1085.e12. PMC: 7510428. DOI: 10.1016/j.cell.2020.09.050. View

15.

Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J . Clinical characteristics of 82 cases of death from COVID-19. PLoS One. 2020; 15(7):e0235458. PMC: 7347130. DOI: 10.1371/journal.pone.0235458. View

16.

Wu C . Focal adhesion: a focal point in current cell biology and molecular medicine. Cell Adh Migr. 2009; 1(1):13-8. PMC: 2633675. DOI: 10.4161/cam.1.1.4081. View

17.

Park E, Myint P, Appiah M, Darkwah S, Caidengbate S, Ito A . The Spike Glycoprotein of SARS-CoV-2 Binds to β1 Integrins Expressed on the Surface of Lung Epithelial Cells. Viruses. 2021; 13(4). PMC: 8069079. DOI: 10.3390/v13040645. View

18.

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J . A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020; 382(8):727-733. PMC: 7092803. DOI: 10.1056/NEJMoa2001017. View

19.

Puerta-Guardo H, Glasner D, Espinosa D, Biering S, Patana M, Ratnasiri K . Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism. Cell Rep. 2019; 26(6):1598-1613.e8. PMC: 6934102. DOI: 10.1016/j.celrep.2019.01.036. View

20.

Buzhdygan T, DeOre B, Baldwin-Leclair A, Bullock T, McGary H, Khan J . The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis. 2020; 146:105131. PMC: 7547916. DOI: 10.1016/j.nbd.2020.105131. View