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Source: COVID-19 Immunology  Jan 24, 2021  3 years, 9 months, 4 weeks, 7 hours, 55 minutes ago

COVID-19 Immunology: Yet Another Study Shows That SARS-CoV-2 Suppresses Human Host Innate Immunity

News Coronavirus
COVID-19 Immunology: Yet Another Study Shows That SARS-CoV-2 Suppresses Human Host Innate Immunity
Source: COVID-19 Immunology  Jan 24, 2021  3 years, 9 months, 4 weeks, 7 hours, 55 minutes ago
COVID-19 Immunology: Another study, this time by scientists from the University of Texas have found that SARS-CoV-2, the virus that causes COVID-19, blocks the processes of innate immune activation that normally direct the production and/or signaling of type I interferon (IFN-I) by the infected cell and tissues.


 
IFN-I is a key component of host innate immunity that is responsible for eliminating the virus at the early stage of infection.
 
The study shows that the SARS-CoV-2 coronavirus has evolved multiple strategies to evade innate immune response to facilitate viral replication, transmission, and pathogenesis. This review summarizes the recent progresses on SARS-CoV-2 proteins that antagonize host IFN-I production and/or signaling. These progresses have provided knowledge for new vaccine and antiviral development to prevent and control COVID-19.
 
The study findings were published in the peer reviewed Journal of Interferon & Cytokine Research (JICR). https://www.liebertpub.com/doi/10.1089/jir.2020.0214#
 
The study found that by suppressing innate immunity, the virus replicates and spreads in the body unchecked, leading to the disease known as COVID-19.
 
The co-researchers Dr Hongjie Xia and Dr Pei-Yong Shi from the University of Texas Medical Branch at Galveston told Thailand Medical News, “The SARS-CoV-2 virus utilizes various approaches to evade host IFN-I response, including suppression of IFN-I production and IFN-I signaling. Viruses defective in antagonizing IFN-I response, in combination with replication-defective mutations, could potentially be developed as live attenuated vaccine candidates."
 
As extracted from the study,  ”The innate interferon (IFN) response constitutes one of the first lines of defense against viral infections. Type I IFN (IFN-I) is a vital component of the early innate immune response that is initiated through multiple host pattern recognition receptors recognizing viral pathogen-associated molecular patterns, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), cytoplasmic DNA receptors, and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs).
 
Upon SARS-CoV-2 infection, the stem loop in genomic RNA and/or double-strand RNA generated in replication are recognized by RIG-I or melanoma differentiation-associated gene 5 (MDA5), inducing a conformation change to expose the caspase activation recruitment domains (CARD) of RIG-I or MDA5.
 
The exposure of CARD could interact with the CARD of the adapter
mitochondrial antiviral signaling protein (MAVS), which subsequently recruits multiple downstream signaling components to the mitochondria, including inhibitor of κ-B kinase ɛ (IKKɛ) and TANK binding kinase 1 (TBK1). Both kinases phosphorylate and activate themselves, such activation leading to phosphorylate the IFN regulatory factor 3 (IRF3). The phosphorylated IRF3 forms homodimer and translocates into nucleus to stimulate IFN-I genes (IFN-α and IFN-β) expression.
 
;Secreted IFN-I binds to the IFN-α and IFN-β receptors on cell surface, leading to activating Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which, in turn, phosphorylate the downstream components, signal transducer, and activator of transcription proteins (STAT1 and STAT2). Phosphorylated STAT1 and STAT2 heterodimerize and interact with IRF9 to form the IFN-stimulated gene factor 3 (ISGF3). The ISGF3 complex undergoes nuclear translocation and binds to IFN-I–stimulated response elements (ISREs), inducing the expression of ISGs with antiviral functions, such as protein kinase R (PKR), 2′,5′-oligoadenylate synthetase (OAS), and RNase L .
 
In response to host immune system, coronaviruses have evolved diverse strategies to suppress the induction of IFN-I and antiviral functions of ISGs.
 
The viruses use the nonstructural proteins, structural proteins
and accessory proteins to disrupt the innate immune system in a variety of ways.
 
Our results indicate that SARS-CoV-2 proteins antagonize distinct steps in IFN-I production and signaling. The findings summarize the antagonism of IFN-I production as such: nsp6 and nsp13 binds to TBK1 to suppress IRF3 and TBK1 phosphorylation, respectively; and OFR6 blocks IRF3 nuclear translocation. 
 
The is also suppression of IFN-I signaling: nsp1, nsp6, nsp13, ORF3a, M, and ORF7b block STAT1 phosphorylation; nsp6, nsp13, ORF7a, and ORF7b suppress STAT2 phosphorylation; and ORF6 inhibits nuclear translocation of STAT1.
 
The  nsp13 and ORF6 of SARS-CoV-2 also antagonize IFN-I response. In addition, it was found that nsp14 and nsp15 also suppressed IFN-β production.
 
The SARS-CoV-2 nsp1, nsp3, nsp12, nsp14, ORF3, ORF6, and M protein inhibited >50% IFN-I induction when activated through RIG-I. These discrepancies could be due to different experimental systems.
 
Several SARS-CoV-2 proteins antagonize multiple steps in the IFN-I production/signaling pathways, including nsp6, nsp13, and ORF6.
 
SARS-CoV nsp6 is a transmembrane protein that rearranges the cellular membrane to form double-membrane vesicles for viral replication.Nsp13 is an RNA helicase that is conserved among coronaviruses. Similarly, hepatitis C virus (HCV) helicase was also shown to bind TBK1 and block TBK1/IRF3 interaction. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.20666
 
Experiments are underway to examine whether the helicase activity of SARS-CoV-2 nsp13 is required for IFN-I antagonism.
 
For nsp6 and nsp13, the molecular mechanisms of their dual activities to bind TBK1 and to suppress STAT1/STAT2 phosphorylation remain to be determined.
 
Studies indicate that ORF6 binds to importin KPNA2 to block nuclear translocation of IRF3 and ISGF3, leading to suppression of both IFN-I production and signaling, respectively. The SARS-CoV-2 ORF6 results are consistent with those of previous studies showing that SARS-CoV ORF6 inhibits both IFN production and STAT1 signaling by interacting with KPNA2 and altering nuclear import.
 
Nsp1 and nsp6 of SARS-CoV-2 suppress IFN-I signaling more efficiently than those of SARS-CoV and MERS-CoV. The biological relevance of this finding was evaluated through a reporter replicon of SARS-CoV-2. Consistent with the greater inhibition of IFN-I signaling by SARS-CoV-2 nsp1 and nsp6, chimeric replicons containing SARS-CoV nsp1 or nsp6 or MERS-CoV nsp6 were more sensitive to IFN-α inhibition. Without IFN-α treatment, the chimeric replicons replicated to the wild-type SARS-CoV-2 replicon level; however, chimeric replicon containing MERS-CoV nsp1 was lethal.The replication capability of chimeric replicons correlated with the relative degree of protein sequence homology of nsp1 or nsp6 among the three viruses.
 
ORF7a and ORF7b, located at the endoplasmic reticulum (ER)-Golgi intermediate compartment, are assembled into SARS-CoV virions; the antagonistic activities of those accessory proteins may facilitate viral replication at the early stage of viral infection. The collective effect from all modulating proteins determines the final antagonism.
 
Different levels of viral replication and immune antagonism could dictate viral transmission and disease development. In support of this notion, when infecting human lung tissues, SARS-CoV-2 produced significantly more virus but less IFN and pro-inflammatory cytokines/chemokines, providing an explanation for asymptomatic transmission and delayed disease onset of COVID-19.
 
Journal of Interferon & Cytokine Research Editor-in-Chief Dr Michael Gale Jr., Department of Immunology and Center for Innate Immunity and Immune Disease, University of Washington added, "Targeting innate immunity is highly attractive for therapeutic and vaccine strategies aimed at controlling SARS-CoV-2 infection and protecting against COVID-19. By revealing how the virus blocks innate immune programs we can then build approaches to restore these processes and enhance antiviral immunity."
 
For more on COVID-19 Immunology, keep on logging to Thailand Medical News.


 

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