Study Find That SARS-Cov-2 Proteins ORF3a And NSP5 Regulate Autophagy Receptor p62 Levels, Decreasing It And Leading To Hyperinflammation States
COVID-19 News - ORF3a And NSP5 Regulate Autophagy Receptor p62 Levels May 01, 2023 1 year, 6 months, 3 weeks, 12 hours, 2 minutes ago
COVID-19 News: Researchers from the University of Belgrade-Serbia, and the University Clinical Center of Serbia have in a new study found that SARS-Cov-2 proteins ORF3a and NSP5 regulate autophagy receptor p62 levels, typically downregulating it and leading to hyperinflammation states.
COVID-19, caused by the SARS-CoV-2 virus, has had a wide range of impacts on patients, from asymptomatic or mild upper respiratory illness to severe pneumonia and organ failure as covered in various past studies and
COVID-19 News reports. The immune system plays a critical role in eliminating the virus and repairing tissue damage. However, when the immune response becomes dysregulated, it can lead to hyperinflammation and organ damage in severe cases.
Autophagy is a cellular process that helps maintain homeostasis by breaking down and recycling damaged proteins and other cellular components. This process is regulated by autophagy-related (ATG) proteins and involves the formation of autophagosomes, vesicles that transport cellular material to lysosomes for degradation. One key autophagy receptor is p62, which helps deliver cargo to autophagosomes.
The relationship between autophagy and virus-induced inflammation is complex. Some viruses, including SARS-CoV-2, can hijack the autophagy process to replicate and evade the host's immune defenses. In this study, the researchers investigated the role of autophagy receptor p62 in the inflammatory response to COVID-19.
The study team measured blood markers of autophagy and cytokine levels in 19 control subjects and 26 COVID-19 patients at hospital admission and one week later.
The study team found that the concentration of p62 was significantly lower in COVID-19 patients at admission and positively correlated with several proinflammatory cytokines. This suggests that the decrease in p62 levels could affect SARS-CoV-2-induced inflammation.
The study also examined the effects of SARS-CoV-2 proteins ORF3a and NSP5 on the expression of proinflammatory cytokines in cell cultures. The results showed that these proteins regulated cytokine expression through the modulation of p62 levels. This supports the involvement of p62 in the inflammatory response to COVID-19.
Previous studies have reported changes in other autophagy markers in COVID-19 patients, but this is the first study to show a significant decrease in p62 levels compared to healthy controls. This decrease was not related to comorbidities, suggesting it is a direct consequence of SARS-CoV-2 infection. Importantly, the levels of other autophagy markers, LC3 and ATG5, were not significantly altered in COVID-19 patients.
The study findings indicate that SARS-CoV-2 proteins ORF3a and NSP5 may regulate p62 levels, potentially affecting the balance between autophagy-dependent and -independent mechanisms. This could impact the overall effect of the infection on p62 levels and, consequently, inflammation. The balance may depend on factors such as cell type, viral load, and infection duration.
The study also confirmed previous reports of increased levels of proinflammatory cytokines in COVID-19 patients, which are associated with disease severity. The positive correlation between p62 levels and proinflammatory cytokines suggests a proinflammatory role for p62 in COVID-19. Future research should investigate the underlying mechanisms involved in p62-dependent
regulation of inflammation.
In conclusion, this study provides new insights into the role of autophagy receptor p62 in the inflammatory response to COVID-19. The decrease in p62 levels in patients and the modulation of p62 by SARS-CoV proteins ORF3a and NSP5 suggest a complex relationship between the virus, autophagy, and inflammation. Understanding this relationship could provide valuable insights into the pathogenesis of COVID-19 and inform the development of novel therapeutic strategies.
To further investigate the role of p62 in the context of COVID-19, additional studies should be conducted with larger patient cohorts and diverse populations. This will enable a more detailed stratification based on clinical and demographic variables, as well as a deeper understanding of the potential impact of p62 on disease severity and progression. Moreover, future research should focus on measuring autophagic flux in blood cells or tissues of COVID-19 patients, as this would provide direct evidence of the involvement of autophagy in the observed changes in p62 levels.
In parallel, in vitro and in vivo models could be used to explore the molecular mechanisms by which SARS-CoV-2 proteins ORF3a and NSP5 modulate p62 levels and their downstream effects on cytokine production. This may help to identify potential therapeutic targets for the modulation of the immune response in COVID-19 patients. Additionally, the development of drugs or small molecules that can modulate p62 levels or its downstream signaling pathways may prove beneficial in managing the hyperinflammatory state associated with severe COVID-19.
Furthermore, investigating the role of p62 in other viral infections could provide a broader understanding of the interplay between autophagy, inflammation, and viral pathogenesis. This knowledge could be leveraged to develop novel antiviral therapies or treatment strategies for a range of infectious diseases.
In summary, the decrease in p62 levels in COVID-19 patients and the modulation of p62 by SARS-CoV-2 proteins ORF3a and NSP5 highlight the importance of further research into the role of autophagy and inflammation in viral infections. A deeper understanding of these processes could lead to the development of innovative therapeutic approaches that target p62 or its downstream signaling pathways to mitigate the severe inflammatory response observed in COVID-19 and other viral infections.
The study findings were published in the peer reviewed journal: cells.
https://www.mdpi.com/2073-4409/12/9/1282
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