scholarly journals Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
James Brett Case ◽  
Yize Li ◽  
Ruth Elliott ◽  
Xiaotao Lu ◽  
Kevin W. Graepel ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Rna Viruses ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Viral Rna ◽  
Wild Type ◽  
Murine Hepatitis Virus ◽  
Antiviral State

ABSTRACTCoronaviruses (CoVs) are positive-sense RNA viruses that infect numerous mammalian and avian species and are capable of causing severe and lethal disease in humans. CoVs encode several innate immune antagonists that counteract the host innate immune response to facilitate efficient viral replication. CoV nonstructural protein 14 (nsp14) encodes 3′-to-5′ exoribonuclease activity (ExoN), which performs a proofreading function and is required for high-fidelity replication. Outside of the orderNidovirales, arenaviruses are the only RNA viruses that encode an ExoN, which functions to degrade double-stranded RNA (dsRNA) replication intermediates. In this study, we tested the hypothesis that CoV ExoN also functions to antagonize the innate immune response. We demonstrate that viruses lacking ExoN activity [ExoN(−)] are sensitive to cellular pretreatment with interferon beta (IFN-β) in a dose-dependent manner. In addition, ExoN(−) virus replication was attenuated in wild-type bone marrow-derived macrophages (BMMs) and partially restored in interferon alpha/beta receptor-deficient (IFNAR−/−) BMMs. ExoN(−) virus replication did not result in IFN-β gene expression, and in the presence of an IFN-β-mediated antiviral state, ExoN(−) viral RNA levels were not substantially reduced relative to those of untreated samples. However, ExoN(−) virus generated from IFN-β-pretreated cells had reduced specific infectivity and decreased relative fitness, suggesting that ExoN(−) virus generated during an antiviral state is less viable to establish a subsequent infection. Overall, our data suggest murine hepatitis virus (MHV) ExoN activity is required for resistance to the innate immune response, and antiviral mechanisms affecting the viral RNA sequence and/or an RNA modification act on viruses lacking ExoN activity.IMPORTANCECoVs encode multiple antagonists that prevent or disrupt an efficient innate immune response. Additionally, no specific antiviral therapies or vaccines currently exist for human CoV infections. Therefore, the study of CoV innate immune antagonists is essential for understanding how CoVs overcome host defenses and to maximize potential therapeutic interventions. Here, we sought to determine the contributions of nsp14 ExoN activity in the induction of and resistance to the innate immune response. We show that viruses lacking nsp14 ExoN activity are more sensitive than wild-type MHV to restriction by exogenous IFN-β and that viruses produced in the presence of an antiviral state are less capable of establishing a subsequent viral infection. Our results support the hypothesis that murine hepatitis virus ExoN activity is required for resistance to the innate immune response.

scholarly journals Mouse hepatitis virus nsp14 exoribonuclease activity is required for resistance to innate immunity

2017 ◽  
Author(s):  
James Brett Case ◽  
Yize Li ◽  
Ruth Elliott ◽  
Xiaotao Lu ◽  
Kevin W. Graepel ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Rna Viruses ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Viral Rna ◽  
Relative Fitness ◽  
Dependent Manner ◽  
Antiviral State

ABSTRACTCoronaviruses (CoV) are positive-sense RNA viruses that infect numerous mammalian and avian species and are capable of causing severe and lethal disease in humans. CoVs encode several innate immune antagonists that interact with the host innate immune response to facilitate efficient viral replication. CoV non-structural protein 14 (nsp14) encodes 3'-to-5' exoribonuclease activity (ExoN), which performs a proofreading function and is required for high-fidelity replication. Outside of the orderNidovirales, arenaviruses are the only RNA viruses that encode an ExoN, which functions to degrade dsRNA replication intermediates. In this study, we tested the hypothesis that CoV ExoN may also function to antagonize the innate immune response. We demonstrate that viruses lacking ExoN activity [ExoN(-)] are sensitive to cellular pretreatment with interferon beta (IFN-β) in a dose-dependent manner. In addition, ExoN(-) virus replication was attenuated in wild-type bone marrow-derived macrophages (BMMs) and partially restored in interferon alpha/beta receptor deficient (IFNAR-/-) BMMs. ExoN(-) virus replication did not result in IFN-β gene expression, and in the presence of an IFN-β-mediated antiviral state, ExoN(-) viral RNA levels were not substantially reduced relative to untreated. However, ExoN(-) virus generated from IFN-β pretreated cells had reduced specific infectivity and decreased relative fitness, suggesting that ExoN(-) virus generated during an antiviral state is less viable to establish a subsequent infection. Overall, our data suggest MHV ExoN activity is required for resistance to the innate immune response and antiviral mechanisms affecting the viral RNA sequence and/or an RNA modification act on viruses lacking ExoN activity.

339 Toll-like receptor mediated innate immune response in hepatocytes suppressed woodchuck hepatitis virus replication via interferon-independent pathway

Cytokine ◽  
2008 ◽  
Vol 43 (3) ◽  
pp. 324
Author(s):  
Xiaoyong Zhang ◽  
Zhongji Meng ◽  
Yang Xu ◽  
Jörg Schlaak ◽  
Michael Roggendorf ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Woodchuck Hepatitis Virus ◽  
Toll Like Receptor

scholarly journals Virucidal Activities of Zinc-Finger Antiviral Proteins and Zinc-Binding Domains for Virus Entry, DNA/RNA Replication and Spread

2020 ◽  
pp. 9-13 ◽  
Author(s):  
Tsuneo Ishida
Keyword(s):  
Immune Response ◽  
Zinc Finger ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Rna Virus ◽  
Virus Entry ◽  
Innate Immune ◽  
Viral Rna ◽  
Zinc Binding ◽  
Corona Virus

The novel EBV (Epstein-Barr virus)-induced ZNFEB including its intronless locus and human protein variants, controls virus entry and exit from cell cycling in activated lymphocytes. ZNF ZCCHC3 binds RNA and facilitates viral RNA that is critical for RLR-mediated innate immune response to RNA virus. ZAP (Zinc-Finger Antiviral Protein) inhibits entry, replication and spread of certain viruses and promotes viral RNA degradation. ZAP may regulate DNA and RNA virus replication that ZAP inhibits Retroviral RNA production and HIV-1(Human Immuno-Deficiency Virus Type 1) infection by promoting the degradation of specific viral mRNAs. Futhermore, ZAP could regulate RNA virus degradation of SARS-CoV's (SARS Corona Virus) and MERS-CoV's (MERS Corona Virus) RNA virus. Replication of SARS-CoV requires proteolytic processing of the replicase polyprotein by a PLpro (Papain-Like Protease) that zinc conjugate inhibits SARSCoV PLpro protease activity. Zinc conjugated complexes as SARS-CoV 3C-like protease inhibitors play important role for this Zn2+-centered coordination pattern that the zinc-coordinating inhibitor is tetrahedrally coordinated. ZBD (Zinc-Binding Domain) is essential for formation of the functional Junin virus envelope glycoprotein complex. Complex ZBD regulates replicative arterivirus helicase and controls mRNA decay helicase. Viral inhibitor p53 down-regulates SARS-CoV replications that p53 inhibits replication of infectious SARS-CoV as well as of replicons and HCoV-NL63 (Human Coronavirus NL63). ZAP-70 kinase regulates HIV cell-to-cell spread that HIV usurps components of the immunological synapse machinery to ensure its own spread through cell-to-cell contacts. Enveloped viruses enter cells and initiate disease-causing cycles of replication that in all cases virus-cell fusion is executed by one or more viral surface glycoproteins denoted as the fusion protein. Virucidal activities of ZNF, ZAP and ZBD are recognised by which Zn2+ ions bind RNA and facilitates viral RNA that is critical for RLR (RIG-1 Like Receptor)-mediated innate immune response to RNA virus and highly diverse fusion proteins have converged on the same overall strategy to mediate a common pathway of membrane fusion, causing to lead enhancement of the anti-viral activity. Zinc ions become used as Zn-coordinated inhibitors for viral regulation of virucidal activities.

The Impact of Defective Viruses on Infection and Immunity

2019 ◽  
Vol 6 (1) ◽  
pp. 547-566 ◽  
Author(s):  
Emmanuelle Genoyer ◽  
Carolina B. López
Keyword(s):  
Immune Response ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Rna Viruses ◽  
Critical Role ◽  
Viral Persistence ◽  
Innate Immune ◽  
Viral Genomes ◽  
The Impact

Defective viral genomes (DVGs) are generated during viral replication and are unable to carry out a full replication cycle unless coinfected with a full-length virus. DVGs are produced by many viruses, and their presence correlates with alterations in infection outcomes. Historically, DVGs were studied for their ability to interfere with standard virus replication as well as for their association with viral persistence. More recently, a critical role for DVGs in inducing the innate immune response during infection was appreciated. Here we review the role of DVGs of RNA viruses in shaping outcomes of experimental as well as natural infections and explore the mechanisms by which DVGs impact infection outcome.

scholarly journals siRNA-Mediated Simultaneous Regulation of the Cellular Innate Immune Response and Human Respiratory Syncytial Virus Replication

Biomolecules ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 165 ◽  
Author(s):  
María Martín-Vicente ◽  
Salvador Resino ◽  
Isidoro Martínez
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Human Respiratory Syncytial Virus ◽  
Innate Immune ◽  
Viral Fusion ◽  
Small Interfering Rnas ◽  
Syncytial Virus ◽  
Nucleoprotein N

Human respiratory syncytial virus (HRSV) infection is a common cause of severe lower respiratory tract diseases such as bronchiolitis and pneumonia. Both virus replication and the associated inflammatory immune response are believed to be behind these pathologies. So far, no vaccine or effective treatment is available for this viral infection. With the aim of finding new strategies to counteract HRSV replication and modulate the immune response, specific small interfering RNAs (siRNAs) were generated targeting the mRNA coding for the viral fusion (F) protein or nucleoprotein (N), or for two proteins involved in intracellular immune signaling, which are named tripartite motif-containing protein 25 (TRIM25) and retinoic acid-inducible gene-I (RIG-I). Furthermore, two additional bispecific siRNAs were designed that silenced F and TRIM25 (TRIM25/HRSV-F) or N and RIG-I (RIG-I/HRSV-N) simultaneously. All siRNAs targeting N or F, but not those silencing TRIM25 or RIG-I alone, significantly reduced viral titers. However, while siRNAs targeting F inhibited only the expression of the F mRNA and protein, the siRNAs targeting N led to a general inhibition of viral mRNA and protein expression. The N-targeting siRNAs also induced a drastic decrease in the expression of genes of the innate immune response. These results show that both virus replication and the early innate immune response can be regulated by targeting distinct viral products with siRNAs, which may be related to the different role of each protein in the life cycle of the virus.

scholarly journals Induction of Siglec-G by RNA Viruses Inhibits the Innate Immune Response by Promoting RIG-I Degradation

Cell ◽  
2013 ◽  
Vol 152 (3) ◽  
pp. 467-478 ◽  
Author(s):  
Weilin Chen ◽  
Chaofeng Han ◽  
Bin Xie ◽  
Xiang Hu ◽  
Qian Yu ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Rna Viruses ◽  
Innate Immune

scholarly journals Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

2021 ◽  
Author(s):  
Vy N. Nguyen ◽  
Salomé Brunon ◽  
Maria N. Pavlova ◽  
Pavlo Lazarchuk ◽  
Roya D. Sharifian ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Replication Forks ◽  
Wild Type ◽  
Feedback Connection ◽  
Pathway Activation ◽  
Foreign Dna ◽  
Sting Pathway

The cGAS/STING pathway, part of the innate immune response to foreign DNA, is known to be activated by cell's own DNA arising from the processing of the genome, including the excision of nascent DNA at arrested replication forks. We found STING activation to affect nascent DNA processing, suggesting a novel, unexpected feedback connection between the two events. Depletion of STING suppressed and re-expression of the protein in STING-deficient cells upregulated degradation of nascent DNA. Fork arrest was accompanied by the STING pathway activation, and a STING mutant that does not activate the pathway failed to upregulate nascent strand degradation. Consistent with this, cells expressing the STING mutant had a reduced level of RPA on parental and nascent DNA of arrested forks as well as a reduced CHK1 activation compared to the cells with wild type STING. Together our findings reveal a novel connection between replication stress and innate immunity.

Sign in / Sign up

Export Citation Format

Share Document