Study Reveals Viral Toxin May Contribute to COVID-19 Severity

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the 2019 coronavirus disease (COVID-19) pandemic. Most people infected with SARS-CoV-2 are asymptomatic or experience mild symptoms, but those who die from severe infection with chronic lung injury and acute respiratory distress syndrome (ARDS) There is also

study: The SARS-CoV-2 spike causes barrier dysfunction and vascular leakage through integrins and TGF-β signaling. Image credit: Billion Photos / Shutterstock.com

Background

Pulmonary pathology reports in severely infected patients showed the development of edema due to epithelial and endothelial barrier dysfunction. Previous studies have found that this condition is caused by an exaggerated inflammatory response, but the exact inducer of epithelial/endothelial hyperpermeability remains unclear.

SARS-CoV-2 is coronavirus family The family possesses a plus-sense ribonucleic acid (RNA) genome that encodes four structural proteins, including the spike (S), membrane (M), nucleocapsid (N), envelope (E), and nonstructural proteins. I’m here.

SARS-CoV-2S glycoproteinis present in the outer coating of the virus and binds to host cell angiotensin-converting enzyme 2 (ACE2) receptors to establish infection. The S protein consists of two domains containing S1 and S2.

S1 contains a receptor-binding domain (RBD) that binds ACE2, and S2 facilitates viral host cell membrane fusion. Cathepsins L, furin-like protease and transmembrane protease, serine 2 (TMPRSS2) are other important host factors in SARS-CoV-2 infection.

In addition to binding to ACE2, S glycoprotein is associated with a variety of other cell surface factors, including integrins and heparan sulfate-containing proteoglycans (HSPGs). These factors primarily facilitate the entry of SARS-CoV-2 into host cells. The association of viral S proteins with these factors has been implicated in signaling pathways that contribute to pulmonary pathology.

During SARS-CoV-2 infection, S1 can shed from the surface of virions after binding to ACE2 receptors. This suggests that shed-S1 may 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 nonstructural protein 1 (NS1) interact with endothelial cells. This interaction induces signaling cascades that promote disruption of cellular structures essential for endothelial barrier integrity associated with the endothelial glycocalyx layer (EGL) and intercellular junctional complexes.

About research

Recent Nature Communications A Study Analyzing Whether the SARS-CoV-2 S Protein Affects Endothelial and Epithelial Barrier Dysfunction in vitro and vascular leakage live.

The authors hypothesized that local concentrations of S protein accumulated in capillaries in tissues were higher than those in patient sera. Therefore, the concentrations of S used in this study were similar to circulating levels in her heavily infected COVID-19 patients.

The concentrations of S used in the experiments ranged from 2.5 μg/mL to 20 μg/mL. However, most experiments were performed at 10 µg/mL.

Main findings

of in vitro When live Experimental findings indicated that virion-associated full-length S, soluble trimeric S and recombinant RBD can cause barrier dysfunction. The first and second mechanisms by which SARS-CoV-2 induces barrier dysfunction are through interaction with ACE2-negative, non-permissive cells and during infection of virus-permissive cells.

A third mechanism responsible for this barrier dysfunction is through shedding of soluble S1 after enzymatic cleavage following ACE2 interaction in cells. The expression of S on the surface of infected cells, which can interact with nearby cells, may also contribute to this phenomenon.

The authors speculated the role of S-mediated barrier dysfunction in the pathogenesis of COVID-19. This is the spread of SARS-CoV-2 from the lungs to the blood and to distant organs. This guess was verified in the following way. live Experiments using mouse models.

To this end, a clinical sample of COVID-19 patients sufficiently promoted barrier dysfunction. Thus, in addition to its role in viral entry into host cells, the S protein also interacts with glycosaminoglycans (GAGs) and integrins, leading to vascular leakage through activation of the transforming growth factor-beta (TGF-β) pathway. provoke.

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

live Experiments similarly showed that SARS-CoV-2 S glycoprotein caused pulmonary vascular leakage in mice, which was reversed by integrins.

Conclusion

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

In the future, further studies should be performed to understand the structural underpinnings of the mechanism.