Effect of SARS-CoV-2 proteins on vascular permeability

Abstract

Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

Cardiovascular Dysfunction in COVID-19: Association Between Endothelial Cell Injury and Lactate

“…Similarly, Feng and colleagues utilized a rhesus macaque model of SARS-CoV-2 respiratory tract infection and observed that SARS-CoV-2 infection significantly reduced VE-cadherin levels in the heart of rhesus macaques when compared to uninfected controls ( 75 ). In agreement with these in vivo observations, several in vitro studies demonstrated that SARS-CoV-2 spike proteins can also disorganize the VE-cadherin complex and decrease VE-cadherin levels in cultured endothelial cells ( 69 , 72 , 74 ). Therefore, SARS-CoV-2 infection can disrupt VE-cadherin largely responsible for the vascular permeability in COVID-19 patients.…”

“…A previous study shows that integrin α5β1 activates NF-κB in ECs to elicit inflammation ( 73 ). Consistently, SARS-CoV-2 protein treatment enhanced p65 nuclear accumulation and IL-6 expression in ECs ( 72 , 74 ). To explore the mechanism of myocardial injury in COVID-19 infected patients, Feng et al.…”

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

“…Virus uptake occurred, but viral replication was not supported. Another study using HUVECs reported that cloned SARS-CoV-2 proteins cause vascular permeability [159]. Resolving these controversies requires further interrogation using physiological human model systems, including more complex organoid models, where the vasculature is embedded within the organoid.…”

Engineered Wnt7a ligands rescue blood brain barrier and neurobehavioral deficits in a mouse model of COVID-19

“…We then asked whether inflammation was restricted to parenchymal or meningeal/ventricular compartments. Barrier forming cells of the cerebrovasculature (Krasemann et al ., 2022; Rauti et al, 2021; Reynolds and Mahajan, 2021), meninges, and choroid plexus (Pellegrini et al, 2020; Yang et al, 2021) are potential targets of SARS-CoV-2 infection and demonstrate inflammatory changes in COVID-19 infected individuals and animal models. We therefore measured foci of inflammation in the BBB, blood-meningeal barrier, and blood-cerebral spinal fluid barrier.…”