SARS-CoV-2 Evades Mucosal Immunity Via ORF8 Protein Downregulating Polymeric Ig Receptor (pIgR) Expression
Nikhil Prasad Fact checked by:Thailand Medical News Team Jun 24, 2024 6 months, 22 hours, 28 minutes ago
COVID-19 News: ORF8 Protein - A Hidden Threat to Our Immune System
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has affected millions of people worldwide. While much of the focus has been on the virus's spike protein, recent research that is covered in this
COVID-19 News report has uncovered another key player in the virus's strategy to infect humans: the ORF8 protein. This lesser-known protein plays a crucial role in weakening our immune system, making it easier for the virus to spread and cause severe illness.
SARS-CoV-2 ORF8 modulates pIgR expression and highjacks the dIgA–pIgR pathway for internalization. Graphical abstract demonstrating the main pathways of pIgR modulation by SARS-COV-2 ORF8. Within cells, ORF8 downregulates pIgR expression, leading to decreased cell surface dIgA binding. In contrast, soluble ORF8 interacts with and highjacks the dIgA–pIgR complex to enter cells (as indicated by the red arrows and “× ”). Whether the immunomodulation of pIgR by ORF8 leads to an antagonized sIgA response remains to be investigated (as indicated with “?”)
The Role of Mucosal Immunity
Our body's first line of defense against respiratory viruses like SARS-CoV-2 is the mucosal immune system. This system includes a receptor called the polymeric immunoglobulin receptor (pIgR), which transports antibodies such as IgA and IgM to the mucosal surfaces of our respiratory tract. These antibodies help neutralize pathogens and prevent infections from taking hold.
ORF8's Sneaky Tactics
Researchers from McGill University-Canada and the Jewish General Hospital in Montreal-Canada have discovered that the SARS-CoV-2 protein ORF8 targets and downregulates pIgR. This means that ORF8 reduces the amount of pIgR available to transport antibodies to the mucosal surfaces. As a result, fewer antibodies reach the mucosal surfaces, leaving them more vulnerable to infection.
How ORF8 Interacts with pIgR
The study found that ORF8 binds directly to pIgR, preventing it from performing its crucial role in the immune response. By interacting with pIgR, ORF8 effectively diminishes the body’s ability to transport protective antibodies to the site of infection. This interaction is particularly troubling because it means the virus can evade the immune system more effectively, leading to more severe infections.
Consistency Across Variants
One of the significant findings of this research is that the ability of ORF8 to downregulate pIgR is consistent across various SARS-CoV-2 variants, including Delta and Gamma. This suggests that ORF8’s role in undermining mucosal immunity is a critical feature of the virus’s strategy, regardless of the variant.
Implications for Health and Treatment
The discovery of ORF8’s role in downregulating pIgR has significant implications for our understanding of COVID-19. It helps explain why some patients experience severe respiratory symptoms and why others might be more susceptible to reinfection or severe illness even after recovering from COVID-19 or receiving a vaccine. This understanding could lead to new treatments that target ORF8 and bolster mucosal immunity.
Potential for Future Research
This new insight into ORF8 and its interaction with pIgR opens up several avenues for future research. Scientists can explore ways to block ORF8 from binding to pIgR, thereby ensuring that antibodies can reach mucosal surfaces and protect against infection. Additionally, understanding this interaction better could help in the development of new therapies that enhance the body’s natural immune response to SARS-CoV-2.
The Broader Impact of ORF8
Beyond its role in downregulating pIgR, ORF8 has been implicated in other immune evasion strategies. For example, ORF8 is known to downregulate major histocompatibility complex class I (MHC-I) molecules, which are crucial for the immune system to recognize and destroy infected cells. By reducing MHC-I levels, ORF8 helps the virus hide from immune cells, allowing it to replicate and spread more easily.
ORF8 and Systemic Effects
ORF8 is not only active within infected cells; it is also secreted and can have systemic effects. This means ORF8 can affect cells that are distant from the initial site of infection, potentially weakening the immune system throughout the body. This systemic action makes ORF8 a particularly insidious component of SARS-CoV-2's strategy to evade the immune system.
Exploring ORF8's Mechanisms
Further research is needed to fully understand the mechanisms by which ORF8 downregulates pIgR and other immune molecules. For instance, it remains unclear whether ORF8 directly causes the degradation of pIgR or if it interferes with its production. Understanding these mechanisms could reveal new targets for antiviral therapies.
Conclusion
The discovery of ORF8’s ability to downregulate pIgR highlights the complex strategies SARS-CoV-2 uses to evade the immune system. By targeting a crucial component of mucosal immunity, the virus increases its chances of establishing infection and causing severe disease. As researchers continue to unravel these mechanisms, they provide valuable insights that could lead to more effective treatments and preventive measures against COVID-19.
The study findings were published in the peer reviewed journal: Viruses.
https://www.mdpi.com/1999-4915/16/7/1008
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https://www.thailandmedical.news/news/covid-19-immunity-scientist-stress-that-emphasis-should-also-be-focused-on-mucosal-immunity-in-order-to-effectively-deal-with-sars-cov-2
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