The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus disease 2019 (COVID-19) pandemic. Although most people infected with SARS-CoV-2 are asymptomatic or experience mild symptoms, some succumb to severe infection with chronic lung injury and acute respiratory distress syndrome (ARDS).
To study: SARS-CoV-2 Spike triggers barrier dysfunction and vascular leakage through integrins and TGF-β signaling. Image Credit: Billion Photos/Shutterstock.com
Background
Reports of lung pathology from severely infected patients indicated the development of edema resulting from dysfunction of the epithelial and endothelial barrier. Although previous studies found that this condition is triggered by a hyperinflammatory response, the exact inducing factor of epithelial/endothelial hyperpermeability remains unclear.
SARS-CoV-2 belongs to the family Coronaviridae and possesses a positive-sense ribonucleic acid (RNA) genome encoding four structural proteins, including spike (S), membrane (M), nucleocapsid ( N) and the envelope (E), and non-structural proteins.
The SARS-CoV-2 S glycoprotein, which is present on the outer coat of the virus, binds to the host cell’s angiotensin-converting enzyme 2 (ACE2) receptors and establishes infection. The S protein consists of two domains, including S1 and S2.
S1 contains the receptor-binding domain (RBD) that binds with ACE2, while S2 promotes fusion of virus host cell membranes. Cathepsin L, furin-like proteases, and transmembrane protease serine 2 (TMPRSS2) are other crucial host factors for SARS-CoV-2 infection.
In addition to binding to ACE2, S-glycoprotein is also associated with several other cell surface factors, such as integrins and heparan sulfate-containing proteoglycans (HSPGs). These factors predominantly promote the entry of SARS-CoV-2 into the host cell. The association of viral protein S with these factors has been linked to signaling pathways that contribute to lung pathology.
During SARS-CoV-2 infection, S1 can be shed from the surface of virions after binding to the ACE2 receptor. This suggests that shed-S1 might also interact with endothelial and epithelial cells; however, the mechanisms behind this interaction are not fully understood. Furthermore, the host factors involved in these interactions have not been identified.
Previous studies have established how viral proteins such as flavivirus non-structural protein 1 (NS1) interact with endothelial cells. This interaction induces signaling cascades that subsequently promote the disruption of cellular structures that are essential for the integrity of the endothelial barrier associated with the endothelial glycocalyx layer (EGL) and intercellular junctional complexes.
About the study
A recent Nature Communications study examined whether the SARS-CoV-2 S protein influences epithelial and endothelial barrier dysfunction in vitro and vascular leakage in vivo.
The authors hypothesized that the local concentration of protein S accumulated in capillaries within tissues would be higher than levels in the serum of patients. Therefore, the concentration of S used in this study was similar to circulating levels in severely infected patients with COVID-19.
The S concentration used for the experiments ranged from 2.5 µg/mL to 20 µg/mL. However, most of the experiments were performed at 10 µg/mL.
key results
Experimental findings in vitro and in vivo indicated that virion-associated full-length S, soluble trimeric S, and recombinant RBD could trigger barrier dysfunction. The first and second mechanisms by which SARS-CoV-2 induces barrier dysfunction is due to its interactions with non-permissive ACE2-negative cells and during infection of virus-permissive cells.
The third mechanism responsible for this barrier dysfunction is through shedding of soluble S1 after enzymatic cleavage following ACE2 interactions in a cell. Expression of S on the surface of infected cells that can interact with nearby cells may also contribute to this phenomenon.
The authors conjectured the role of S-mediated barrier dysfunction in the pathogenesis of COVID-19, which is the spread of SARS-CoV-2 from the lungs to the blood and then to distal organs, the latter of which it is where the accommodating cells of the virus reside. . This conjecture was validated through in vivo experiments using a mouse model.
To do this, clinical samples from patients with COVID-19 sufficiently facilitated barrier dysfunction. Therefore, in addition to its role in virus entry into the host cell, the S protein also interacts with glycosaminoglycans (GAGs) and integrins to induce vascular leakage through activation of the transforming growth factor beta pathway ( TGF-β).
Transcriptional analyzes demonstrated that S-glycoprotein regulates the expression of transcripts involved in the modulation of the extracellular matrix (ECM). Experimental analysis clarified the underlying mechanisms, in which TGF-β, GAGs, and integrins were associated with barrier dysfunction.
In vivo experiments similarly demonstrated that the SARS-CoV-2 S glycoprotein triggers vascular leakage in the lungs of mice, which was reversed by integrins.
conclusions
Taken together, the current study provided the mechanistic explanation for TGF-β overproduction during COVID-19, which has been correlated with disease severity. Furthermore, S and SARS-CoV-2 full-length RBDs can independently mediate barrier dysfunction and vascular leakage.
In the future, more research should be done to understand the structural basis of the mechanisms.
Magazine reference:
Biering, SB, Gomes de Sousa, FT, Tjang, LV, et al. (2022) SARS-CoV-2 Spike triggers barrier dysfunction and vascular leakage through integrins and TGF-β signaling. Nature Communications 13 (7630). doi:10.1038/s41467-022-34910-5
Source: news.google.com