Research finds viral toxin may contribute to severity of COVID-19

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the coronavirus disease 2019 (COVID-19) pandemic. Although most people infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some succumb to severe infection with chronic lung damage and acute respiratory distress syndrome (ARDS).

Study: SARS-CoV-2 Spike triggers barrier dysfunction and vascular leakage via integrins and TGF-β signaling. Image Credit: Billion Photos / Shutterstock.com

Background

Reports of pulmonary pathology from severely infected patients have indicated the occurrence of edema resulting from dysfunction of the epithelial and endothelial barrier. Although previous studies have shown 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 Coronaviridae family and has a positive-sense ribonucleic acid (RNA) genome that encodes four structural proteins, including tip (S), membrane (M), nucleocapsid (N), and envelope (E), and proteins not structural.

SARS-CoV-2 S glycoprotein, which is present in the outer envelope of the virus, binds to the host cell’s angiotensin-converting enzyme 2 (ACE2) receptors and establishes the infection. The S protein consists of two domains including S1 and S2.

S1 contains the receptor binding domain (RBD) that binds to 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 various other cell surface factors, such as integrins and heparan sulfate-containing proteoglycans (HSPG). These factors mainly 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 cleared 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. Moreover, the host factors involved in these interactions have not been identified.

Previous studies have established how viral proteins like flavivirus non-structural protein 1 (NS1) interact with endothelial cells. This interaction induces signaling cascades that subsequently promote the disruption of cellular structures essential for the integrity of the endothelial barrier associated with the endothelial layer of the glycocalyx (EGL) and intercellular junctional complexes.

About the study

A recent Nature Communication a study analyzed whether the SARS-CoV-2 S protein influences endothelial and epithelial barrier dysfunction in vitro and vascular leakage Direct.

The authors hypothesized that the local concentration of the protein S accumulated in the capillaries of the tissues would be higher than the levels in the serum of the patients. Therefore, the concentration of S used in this study was similar to circulating levels in severely infected COVID-19 patients.

The concentration of S used for the experiments ranged from 2.5 µg/mL to 20 µg/mL. However, most experiments were conducted at 10 µg/mL.

Main conclusions

The in vitro and Direct experimental findings 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 are due to its interactions with non-permissive ACE2 negative cells and during infection of permissive cells with the virus.

The third mechanism responsible for this barrier dysfunction is the excretion of soluble S1 after enzymatic cleavage following ACE2 interactions on a cell. Expression of S on the surface of infected cells which can interact with neighboring 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 the distal organs, the latter being the location where the complacent virus cells reside. . This conjecture has been validated by Direct experiments on a mouse model.

To this end, clinical samples from COVID-19 patients have sufficiently facilitated barrier dysfunction. Thus, in addition to its role in viral entry into the host cell, protein S also interacts with glycosaminoglycans (GAGs) and integrins to induce vascular leakage via activation of the transforming growth factor beta pathway ( TGF-β).

Transcriptional analyzes have demonstrated that glycoprotein S regulates the expression of transcripts involved in the modulation of the extracellular matrix (ECM). Experimental analysis elucidated the underlying mechanisms, in which TGF-β, GAGs and integrins were associated with barrier dysfunction.

Direct experiments also demonstrated that the SARS-CoV-2 S glycoprotein triggers vascular leakage in mouse lungs, which was reversed by integrins.

conclusion

Taken together, the current study provided the mechanistic explanation for TGF-β overproduction during COVID-19, which was correlated with disease severity. Moreover, the full-length S and RBD of SARS-CoV-2 can independently mediate barrier dysfunction and vascular leakage.

In the future, more research needs to be conducted to understand the structural basis of the mechanisms.