SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

Abstract

SummarySevere 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.

Integrins as Therapeutic Targets for SARS-CoV-2

“…While vaccination combined with other mitigation strategies such as mask-wearing, avoiding large indoor crowds in poorly ventilated locations, and social distancing continue to be the most effective COVID-19 preventative approaches, new therapeutic strategies remain attractive. The evidence clarifies that the spike protein of SARS-CoV-2, through its integrin-binding RGD motif, allows integrins to mediate SARS-CoV-2 infection and spike-mediated endothelial dysfunction ( Biering et al., 2021 ; Robles et al., 2022 ). What remains is to delineate how integrins participate in cell entry and trafficking of the virus, and ultimately, determine whether specific integrins, such as α 5 β 1 , αVβ3, or a group of integrins, play a crucial role in mediating infection.…”

“…In endothelial cells, integrins regulate barrier integrity by mediating intracellular signaling cascades triggered upon ligand binding. Through its RGD motif, SARS-CoV-2 spike protein induces significant cellular permeability and vascular dysregulation through the downregulation or internalization of junction proteins, to include VE-Cadherin endothelial adherens junction protein, JAM-A tight junctional protein, Connexin-43 gap junctional protein, and Platelet endothelial cell adhesion molecule-1 (PECAM-1) in primary mouse brain microvascular endothelial cells ( Biering et al., 2021 ; Raghavan et al., 2021 ). Strikingly, integrin α 5 β 1 activation by spike protein induces an endothelial inflammatory phenotype characterized by increased leukocyte attachment to the endothelium and the expression of inflammatory cytokines and coagulation factors ( Robles et al., 2022 ).…”

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…As shown in Figure 9 , common hubs were predicted for each SARS-CoV-2 structural protein such as TGFB1/B3, SMAD and TEAD proteins, EGF, SPP1 and EDN1. It has been previously observed that SARS-CoV-2 N protein interacts with SMAD proteins enhancing TGF-beta signaling ( 84 ) whereas SARS-CoV-2 S protein triggers a transcriptional response associated to TGF-beta signaling ( 85 ). Interestingly, a therapeutic strategy focused on the inactivation of TGF-beta using integrin inhibitors has been proposed to mitigate COVID-19 severity ( 86 ).…”

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…As shown in Figure 9 , common hubs were predicted for each SARS-CoV-2 structural protein such as TGFB1/B3, SMAD and TEAD proteins, EGF, SPP1 and EDN1. It has been previously observed that SARS-CoV-2 N protein interacts with SMAD proteins enhancing TGF-beta signaling (Wang et al, 2022) whereas SARS-CoV-2 S protein triggers a transcriptional response associated to TGF-beta signaling (Biering et al, 2021). Interestingly, a therapeutic strategy focused on the inactivation of TGF-beta using integrin inhibitors has been proposed to mitigate COVID-19 severity (Huntington et al, 2022).…”