Shandong University Study Uncovers That SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons By Targeting Components Of Signaling Pathways!
: Chinese scientist from Shandong University in Jinan-China have discovered that the SARS-CoV-2 ORF9b proteins are able to inhibit type I and III interferon (IFN) response and production by targeting various components of various immune signaling pathways.
The study findings were published in the peer reviewed Journal of Medical Virology. https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.27050
It must be noted that Thailand Medical News has always been calling for researchers to pay more attention to recently discovered ORFs (open reading frames) in the SARS-CoV-2 genome such as ORF10, ORF9b, and ORF9c not only for genomic surveillance but also their involvement in pathogenesis and how their proteins affect the various human host cellular pathways. T
he assignment of the mutations in these ORFs may reveal further differences between SARS-CoV-2 variants and also constitute critical data, something that is significantly missing in the GISAID platform.
To date it has only been researchers from China that have been focused on the study and influence of these ORFs.
To date, various clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19.
But how exactly the SARS-CoV-2 virus is able to evades antiviral immunity still remains unanswered with many hypothesis that are still not properly verified, hence needing further investigations.
The study team reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways.
According to the study findings, the SARS-CoV-2 ORF9b proteins impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C).
It was found that the SARS-CoV-2 ORF9b proteins inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKKε rather than IRF3-5D, the active form of IRF3.
Furthermore the SARS-CoV-2 ORF9b proteins also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively.
It should also be noted that another past study also by Chinese researchers published in the peer reviewed journal: Cellular and Molecular Immunology by Nature, also showed that the SARS-CoV-2 ORF9b suppresses interferon 1. https://www.nature.com/articles/s41423-020-0514-8
Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation.
Another previous Chinese study has also showed that SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling. https://pubmed.ncbi.nlm.nih.gov/33567255/
Interestingly, it was found that the overexpression of SARS-CoV-2 ORF9b proteins facilitates the replication of the vesicular stomatitis virus.
Hence the study team concluded that SARS-CoV-2 ORF9b proteins negatively regulate antiviral immunity, facilitating virus replication.
It must also be noted that the SARS-CoV-2 is more sensitive to IFN treatment than other coronaviruses, multiple viral proteins become more critical to suppress IFN production at different steps to ensure the production and function of IFNs are minimized during SARS-CoV-2 infection. https://pubmed.ncbi.nlm.nih.gov/32938761/
The SARS-COV-2 ORF9b targets multiple proteins of the distinct immune signaling pathways, which may suppress IFN signaling at different steps.
Similarly, SARS-CoV- 2 ORF6 and MERS-CoV ORF4b are capable of perturbing multiple innate antiviral signaling pathways by target various components of these pathways. https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1780953
Although cGAS-STING is cytosolic dsDNA sensing pathway, coronaviruses, a family of RNA viruses, also encode viral proteins such as papain-like protease to impair STING function; thus, this pathway is essential in defending against coronavirus infection. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030802
The study team pointed out that since the inhibition of cGAS-STING pathway by SARS-CoV-2 5 ORF9b may suggest that this pathway may play a role in SARS-CoV-2 clearance, drugs or chemicals such as 2’-3’cGAMP that activates this pathway may be considered for use in COVID-19 treatments.
The study team added, “Although the administration of exogenous IFNs is show to be valid for SARS-CoV2 clearance on both SARS-CoV-2 patients and cell models, full evaluation of this treatment requires extensive studies on the relative importance of all IFN-antagonizing viral proteins encoded by SAR-CoV-2. Thus, our findings that the SARS-COV-2 ORF9b suppresses type I and III IFN production contribute to our understanding of the pathogenesis of COVID-19, and the identification of multiple protein targets may provide more precise treatment of COVID-19.The study findings contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impairs antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.”
Thailand Medical News would like to add that the genome of SARS-CoV-2 is about 30 kb in length encoding 14 putative open reading frames, including the large replicase genes expressing two replicative polyproteins (pp1a and pp1ab) that would be cleaved into NSP1-16 by viral proteases, the structural genes expressing spike (S), membrane (M), envelop (E), and nucleocapsid (N) protein, and the accessory genes expressing ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c, and ORF10.
To date, we still do not know much about all these ORFs and also about the rest of the proteins on the genome besides the Spike proteins. The old school of virology which only focuses on certain proteins can no longer hold in the case of the SARS-CoV-2 virus when in comes to genomic surveillance, understanding the virus transmissibility, virulence, immune evasive characteristics, pathogenesis, influence on various human host cellular pathways and the development of therapeutics including vaccines.
Although the accessory proteins of coronaviruses are not essential for viral replication and virion assembly, they contribute to the virulence by affecting the virus release, stability, and pathogenesis. To date, the function of SARS-CoV-2 accessory proteins in immune evasion is still not properly understood and warrants more studies.
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