SARS-CoV-2 Orf8 protein forms intracellular aggregates and disrupts lung cell immunity
Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 12, 2024 3 months, 2 weeks, 3 days, 20 hours, 9 minutes ago
COVID-19 News: In a recent study, researchers have discovered crucial insights into how the SARS-CoV-2 virus, responsible for COVID-19, manipulates lung cells to evade the immune system. This
COVID-19 News report explores the findings of this study, which highlight the significant role of the ORF8 protein in disrupting antiviral defenses in human lung epithelial cells.
SARS-CoV-2 Orf8 protein forms intracellular aggregates and disrupts lung cell immunity
Thailand Medical News had previously covered other studies that showed how the SARS-CoV-2 Orf8 proteins evades or disrupts various other host immune related defenses.’
https://www.thailandmedical.news/news/sars-cov-2-evades-mucosal-immunity-via-orf8-protein-downregulating-polymeric-ig-receptor-pigr-expression
https://www.thailandmedical.news/news/covid-19-news-oligomer-formation-of-sars-cov-2-orf8-through-73yidi76-motifs-regulates-immune-response-and-non-infusion-antiviral-interactions
https://www.thailandmedical.news/news/sars-cov-2-news-scientist-from-india-find-that-sars-cov-2-orf8-protein-possesses-complement-inhibitory-properties
https://www.thailandmedical.news/news/unique-sites-of-immune-regulation-discovered-in-sars-cov-2-orf8
https://www.thailandmedical.news/news/covid-19-news-study-discovers-that-sars-cov-2-orf8-protein-exhibits-complement-inhibitory-properties-and-damages-innate-immunity
https://www.thailandmedical.news/news/covid-19-news-yale-study-shows-that-omicron-subvariants-are-evolving-further-through-mutations-on-orf8-proteins-to-escape-from-mhc-i-recognition
What is ORF8?
The ORF8 protein is an accessory protein encoded by the SARS-CoV-2 genome. Unlike other viral proteins, ORF8 has unique characteristics that enable it to form aggregates within the ce
lls it infects. Researchers from the Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, University of Chicago, and Jesse Brown Veterans Affairs Medical Center collaborated to understand the function of ORF8 and its impact on lung cell immunity.
Formation of Intracellular Aggregates
Using advanced imaging techniques, the research team observed that ORF8 forms distinctive aggregates in both the cytoplasm and nucleus of lung epithelial cells. These aggregates, as predicted by bioinformatic analysis, result from specific N-terminal residues of the ORF8 protein. Interestingly, the formation of these aggregates occurs independently of the inflammatory response typically triggered by viral infections.
Impact on Cell Proliferation and Cycle
One might expect that such intracellular aggregates would hinder cell growth or disrupt the cell cycle. However, the study found that ORF8 expression does not significantly affect the proliferation or cell cycle progression of lung epithelial cells. This suggests that the aggregates themselves are not directly toxic to the cells, allowing the virus to manipulate the host cell machinery without causing immediate cell death.
Disruption of Antiviral Immunity
The most striking finding of the study is how ORF8 affects the cell's antiviral immune response. Normally, cells have a baseline expression of antiviral molecules ready to combat infections. However, ORF8 significantly reduces the expression of several critical antiviral genes such as DHX58, ZBP1, MX1, and MX2. These genes play vital roles in recognizing and responding to viral infections, and their suppression by ORF8 gives SARS-CoV-2 a substantial advantage in evading the immune system.
Selective Inhibition of IFNγ Response
Interferons (IFNs) are crucial for the antiviral response. While both IFNγ and IFNβ are important, the study found that ORF8 selectively inhibits the IFNγ-induced expression of antiviral genes in lung epithelial cells. This selective inhibition suggests that ORF8 specifically targets pathways involved in the IFNγ response, further aiding the virus in avoiding detection and destruction by the immune system.
Broader Implications
The findings from this study have broader implications for understanding the pathogenesis of COVID-19. The ability of ORF8 to form aggregates and selectively inhibit antiviral responses highlights a sophisticated mechanism by which SARS-CoV-2 can persist in the host and cause prolonged disease. This understanding opens new avenues for potential therapeutic interventions targeting ORF8 to bolster the host's antiviral defenses.
Future Research Directions
The study raises several questions for future research. One area of interest is whether ORF8 expression persists in patients who have recovered from COVID-19 and if it plays a role in long-haul COVID-19 symptoms. Additionally, understanding the precise molecular mechanisms by which ORF8 forms aggregates and inhibits IFNγ responses could lead to the development of novel treatments aimed at mitigating the effects of this viral protein.
Conclusion
This study sheds light on the critical role of the SARS-CoV-2 ORF8 protein in disrupting antiviral immunity in lung epithelial cells. By forming intracellular aggregates and selectively inhibiting key antiviral pathways, ORF8 allows the virus to evade the immune system and persist in the host.
The study findings were published in the peer-reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.679482/full
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