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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB

View ORCID ProfileJuan Pablo Robles, View ORCID ProfileMagdalena Zamora, View ORCID ProfileGonzalo Martinez de la Escalera, View ORCID ProfileCarmen Clapp
doi: https://doi.org/10.1101/2021.08.01.454605
Juan Pablo Robles
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, México
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  • For correspondence: juanpabloroblesa@gmail.com
Magdalena Zamora
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, México
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Gonzalo Martinez de la Escalera
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, México
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Carmen Clapp
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, México
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Abstract

Vascular endothelial cells (EC) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, the hallmarks of the severe disease. However, the mechanisms by which EC are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin α5β1 signaling. Incubation of human umbilical vein EC with whole spike, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and enhanced the expression of leukocyte adhesion molecules VCAM1 and ICAM1, the adhesion of peripheral blood leukocytes, and the permeability of the monolayer. Inhibitors of integrin α5β1 activation prevented these effects. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin α5β1 in EC to activate Rho GTPases, eNOS pathways, and the NF-κB gene expression program responsible for vascular leakage and leukocyte infiltration, respectively. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin α5β1 as a promising target for treating vascular inflammation in COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 02, 2021.
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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB
Juan Pablo Robles, Magdalena Zamora, Gonzalo Martinez de la Escalera, Carmen Clapp
bioRxiv 2021.08.01.454605; doi: https://doi.org/10.1101/2021.08.01.454605
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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB
Juan Pablo Robles, Magdalena Zamora, Gonzalo Martinez de la Escalera, Carmen Clapp
bioRxiv 2021.08.01.454605; doi: https://doi.org/10.1101/2021.08.01.454605

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