COVID-19 Latest: Yet Another Way SARS-CoV-2 Evades Immune Response, This Time By Using Its Orf6 Protein To Hijack The Nup98 Pathway
: A new study led by researchers from Icahn School of Medicine-Mount Sinai with the support of scientist from University of Texas Southwestern Medical Center, University of Alberta-Canada, Vanderbilt University School of Medicine and Sanford Burnham Prebys Medical Discovery Institute, La Jolla- California have uncovered yet another way the SARS-CoV-2 is able to evade human host immune response this time by blocking interferon signaling through using its Orf6 protein to hijack the Nup98 pathway.
SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host.
In this study, the researchers show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs).
The study findings demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. The study team found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, they show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together this study data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
The research findings are published in the peer reviewed journal of the Proceedings of the National Academy of Sciences. https://www.pnas.org/content/117/45/28344
In order to successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that the viral accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able to inhibit STAT1 nuclear translocation to block IFN signaling. https://www.sciencedirect.com/science/article/pii/S2211124720312237
The study team reports that Orf6 localizes at the nuclear pore complex (NPC) where it binds directly to the Nup98-Rae1 complex to target the nuclear import pathway and mediate this inhibition. A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines.
The SARS-CoV-2 coronavirus belongs to the Betacoronavirus genus. Belonging to the same genus are SARS-CoV, with 79 percent genetic similarity, and Middle East respiratory syndrome coronavirus (MERS-CoV), with about 50 percent similarity. These viruses cause both upper and lower respiratory tract infections and may lead to severe and even life-threatening respiratory syndrome in humans. This condition often leads to a deranged immune response that can raise the levels of proinflammatory cytokines, cause a&n
bsp;cytokine storm, and cause severe tissue damage.
Typically Interferons (IFNs) or cytokines released in response to the infection are classified into three groups:
-IFN-I (type I IFNs) – produced by any nucleated cell type and signal through the type I IFN receptor (IFNAR)
-IFN-II (type II IFNs) - produced by specialized immune cells and signal through IFN-γ receptor (IFNGR). They synergize between innate and adaptive immune responses
-IFN-III (type III IFNs) - bind to the IFN-λ receptor (IFNLR) found on epithelial cells seen in the respiratory and gastrointestinal tracts.
Type I and type III IFNs can be stimulated by pathogen-associated molecular patterns (PAMPs) using pattern recognition receptors (PRRs).
When the receptors bind, the two IFNs activate the JAK-STAT signaling cascade and activate STAT1 and STAT2 to form the IFN-stimulated gene factor 3 (ISGF3) transcriptional complex.
ISGF3 enters the nucleus by the karyopherin alpha 1 (KPNA1)-karyopherin beta 1 (KPNB1) heterodimer https://www.embopress.org/doi/full/10.1093/emboj/21.7.1754
It has been found that these karyopherins mediate cytoplasmic-nuclear translocation after interacting with proteins of the nuclear pore complex (NPC) termed nucleoporins or Nups
Within the nucleus, the ISGF3 binds to specific IFN-stimulated response elements (ISREs) in the DNA. This triggers the transcription of IFN-stimulated genes (ISGs), and the antiviral response is generated.
However STAT1, on the other hand, enters the nucleus and stimulates the ISGs by binding to gamma-activated site (GAS) promoter elements in the genes.
The study team explained that in SARS and COVID-19 patients, the levels of IFNs are low, and there are high levels of chemokines. In lab mice, it has been seen that IFN-I signaling was needed for ISG induction and proinflammation. This signaling was not responsible for controlling virus replication.
Thus SARS-CoV-2 was found to be resistant to IFN signaling. The team explains that accessory proteins Orf3b and Orf6 can inhibit IFN production and signaling. Thus the team speculates that evading the IFN-mediated antiviral signaling could help replication of SARS-CoV-2 and lead to its pathogenesis within the human host.
This research attempted to see if the SARS-CoV-2 could block the STAT1 and STAT2 nuclear translocation so as to block the induction of IFN-stimulated genes (ISGs).
Co researcher Dr Yi Ren, assistant professor of biochemistry, at Vanderbilt University researcher has undertaken previous work with influenza A and the vesicular stomatitis virus (VSV). These viruses also signal proteins such as interferons that mount an antiviral reaction.
Dr Ren told Thailand Medical News, , “From the literature review, I understood that I had the requisite specialist knowledge of how protein expression is blocked in VSV to meaningfully contribute to COVID-related research. We were able to test the direct interaction between the host factor that I work with and the SARS-CoV-2 protein. We found that, indeed, they interact.”
It was found that the viral accessory protein Orf6 helps in exerting an anti-IFN activity.
Furthermore SARS-CoV-2 Orf6, found in the nuclear pore complex (NPC), was observed to interact with the Nup98-Rae1 using its C-terminal domain. This blocks the formation of the cargo-receptor (karyopherin/importin) complex and disrupts the importation of the complex into the nucleus of the cell.
Also it was discovered that if a substitution at residue 58 from methionine-to-arginine was made in the Orf6, its binding to the Nup98-Rae1 complex is impaired. This blocks the IFN antagonistic function.
The study team concluded that a mechanism of viral antagonism is possible. In this, the virus can “hijack” the Nup98-Rae1 complex so that the host system cannot mount an antiviral reaction against the virus using the IFNs.
The team wrote, “A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines.”
Dr Ren added, “Even though SARS-CoV-2 is an entirely new virus that the world is grappling with, it deploys a similar strategy to target the same host factor as VSV, making me feel somewhat familiar with the virus. After so many years of studying influenza A and VSV, to see such a small difference on a cellular level resulting in what we’ve seen during this pandemic puts these ‘small’ differences into perspective.”
Importantly, the study data also show that SARS-CoV-2 infection triggers a dramatic reduction of total RNA content in infected cells as compared to uninfected or bystander cells. This strongly suggests that viral infection results in extensive transcriptional dysregulation and host gene suppression that is likely due to the combined action of multiple viral factors, including Orf6.
Nevertheless, the Orf6-mediated suppression of IFN signaling in infected tissues is likely to promote viral replication and to play an important role in the pathogenesis of COVID-19. Therefore, it will be important in the near future to address the contribution of Orf6 to the in vivo pathogenesis of SARS-CoV-2.
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