scholarly journals STING-dependent translation inhibition restricts RNA virus replication

2018 ◽  
Vol 115 (9) ◽  
pp. E2058-E2067 ◽  
Author(s):  
Kate M. Franz ◽  
William J. Neidermyer ◽  
Yee-Joo Tan ◽  
Sean P. J. Whelan ◽  
Jonathan C. Kagan
Keyword(s):  
Virus Infection ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Rna Virus ◽  
Virus Infections ◽  
Dna Viruses ◽  
Translation Inhibition ◽  
Basal Expression ◽  
Antiviral Activities ◽  
Mitochondrial Antiviral Signaling

In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I–like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP–AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.

Exploration of the in vitro cytotoxic and antiviral activities of different medicinal plants against infectious bursal disease (IBD) virus

2014 ◽  
Vol 9 (5) ◽  
pp. 531-542 ◽  
Author(s):  
Waqas Ahmad ◽  
Sohail Ejaz ◽  
Khaleeq Anwar ◽  
Muhammad Ashraf
Keyword(s):  
Medicinal Plants ◽  
Colorimetric Assay ◽  
Rna Virus ◽  
Infectious Bursal Disease ◽  
Dna Viruses ◽  
Mtt Colorimetric Assay ◽  
Bursal Disease ◽  
Dried Fruit ◽  
Antiviral Activities

AbstractInfectious bursal disease (IBD) caused by non-enveloped double stranded RNA virus is an acute and contagious poultry disease. Outbreak of IBD could result in 10–75% mortality of the birds; hence it has gained socio-economic importance worldwide. Medicinal plants have shown broad spectrum anti-viral activities against RNA and DNA viruses. Moringa oleifera Lam (MOL), Phyllanthus emblicus Linn (PEL), Glycyrrhiza glabra Linn (GGL), and Eugenia jambolana Lam (EJL) are commonly available medicinal plants of the sub-continent and exhibited anti-viral potential against different viruses. Ethanolic extracts of the leaves of MOL and EJL, roots of GGL and dried fruit of PEL were investigated for their cytotoxic and anti-viral potential against IBD virus using MTT colorimetric assay and anti-viral assay. Significant anti-viral potential (P<0.001) was demonstrated at concentrations 12.5, 25, 50 and 100 µg ml−1 of GGL, PEL, MOL and EJL, respectively, with no cytotoxicity. Data also spotlighted that all tested plant extracts possess significant anti-viral potential and this trend was higher in GGL followed by PEL, MOL, and EJL. The data undoubtedly conclude that these medicinal plants contain several health beneficial phyto-chemicals which got significant anti-viral potential and effectively be utilized against IBD virus. Moreover, the outcomes of this study provide a platform on the way to discover novel anti-viral agents against IBD virus and other viruses from plant origin.

scholarly journals Analysis of Porcine RIG-I Like Receptors Revealed the Positive Regulation of RIG-I and MDA5 by LGP2

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuangjie Li ◽  
Jie Yang ◽  
Yuanyuan Zhu ◽  
Hui Wang ◽  
Xingyu Ji ◽  
...  
Keyword(s):  
Cell Activation ◽  
Viral Infections ◽  
Rna Virus ◽  
Gene Knockout ◽  
Constitutive Activity ◽  
Virus Infections ◽  
Positive Regulation ◽  
Dsrna Binding ◽  
Livestock Animal ◽  
Signaling Activity

The RLRs play critical roles in sensing and fighting viral infections especially RNA virus infections. Despite the extensive studies on RLRs in humans and mice, there is a lack of systemic investigation of livestock animal RLRs. In this study, we characterized the porcine RLR members RIG-I, MDA5 and LGP2. Compared with their human counterparts, porcine RIG-I and MDA5 exhibited similar signaling activity to distinct dsRNA and viruses, via similar and cooperative recognitions. Porcine LGP2, without signaling activity, was found to positively regulate porcine RIG-I and MDA5 in transfected porcine alveolar macrophages (PAMs), gene knockout PAMs and PK-15 cells. Mechanistically, LGP2 interacts with RIG-I and MDA5 upon cell activation, and promotes the binding of dsRNA ligand by MDA5 as well as RIG-I. Accordingly, porcine LGP2 exerted broad antiviral functions. Intriguingly, we found that porcine LGP2 mutants with defects in ATPase and/or dsRNA binding present constitutive activity which are likely through RIG-I and MDA5. Our work provided significant insights into porcine innate immunity, species specificity and immune biology.

Mechanisms of Action of Ribavirin in Antiviral Therapies

2001 ◽  
Vol 12 (5) ◽  
pp. 261-272 ◽  
Author(s):  
Robert C Tam ◽  
Johnson YN Lau ◽  
Zhi Hong
Keyword(s):  
Hepatitis C ◽  
Viral Infections ◽  
Rna Virus ◽  
Lassa Fever ◽  
Biological Properties ◽  
Interferon Α ◽  
Hepatitis C Infection ◽  
Antiviral Activities ◽  
Syncytial Virus

Although ribavirin was originally synthesized over 30 years ago and has been used to treat viral infections as monotherapy (respiratory syncytial virus and Lassa fever virus) or with interferon-α (IFN-α) as combination therapy (hepatitis C virus), the precise mechanism of its therapeutic activities remains controversial. In this review we focus on two main biological properties of ribavirin: its indirect and direct antiviral activities (with particular emphasis on its efficacy against chronic hepatitis C infection). Each property could individually or collectively account for its clinical efficacy against viral infections. First, with emphasis on the evidence for indirect activities of ribavirin, we will review the clinical observations that suggest that the immunomodulatory properties of ribavirin can in part account for its antiviral activities in vivo. We will then describe the mode of ribavirin's direct antiviral activities. These direct activities can be ascribed to several possible mechanisms, including the recently described activity as an RNA mutagen, a property that may be important in driving a rapidly mutating RNA virus over the threshold to ‘error catastrophe′.

scholarly journals BPIFB3 interacts with ARFGAP1 and TMED9 to regulate non-canonical autophagy and RNA virus infection

2020 ◽  
pp. jcs.251835
Author(s):  
Azia S. Evans ◽  
Nicholas J. Lennemann ◽  
Carolyn B. Coyne
Keyword(s):  
Mass Spectrometry ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Rna Viruses ◽  
Rna Virus ◽  
Negative Regulator ◽  
Host Factors ◽  
Important Negative Regulator ◽  
Cellular Components

Autophagy is a degradative cellular pathway that targets cytoplasmic contents and organelles for turnover by the lysosome. Various autophagy pathways play key roles in the clearance of viral infections, and many families of viruses have developed unique methods for avoiding degradation. Some positive stranded RNA viruses, such as enteroviruses and flaviviruses, usurp the autophagic pathway to promote their own replication. We previously identified the endoplasmic reticulum-localized protein BPIFB3 as an important negative regulator of non-canonical autophagy that uniquely impacts the replication of enteroviruses and flaviviruses. Here, we find that many components of the canonical autophagy machinery are not required for BPIFB3 depletion induced autophagy and identify the host factors that facilitate its role in the replication of enteroviruses and flaviviruses. Using proximity-dependent biotinylation (BioID) followed by mass spectrometry, we identify ARFGAP1 and TMED9 as two cellular components that interact with BPIFB3 to regulate autophagy and viral replication. Importantly, our data demonstrate that non-canonical autophagy in mammalian cells can be controlled outside of the traditional pathway regulators and define the role of two proteins in BPIFB3 depletion mediated non-canonical autophagy.

scholarly journals Antiviral activities of ISG20 in positive-strand RNA virus infections

Virology ◽  
2011 ◽  
Vol 409 (2) ◽  
pp. 175-188 ◽  
Author(s):  
Zhi Zhou ◽  
Nan Wang ◽  
Sara E. Woodson ◽  
Qingming Dong ◽  
Jie Wang ◽  
...  
Keyword(s):  
Rna Virus ◽  
Virus Infections ◽  
Positive Strand ◽  
Antiviral Activities ◽  
Positive Strand Rna Virus ◽  
Positive Strand Rna

scholarly journals Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen

2021 ◽  
Author(s):  
Alice Mac Kain ◽  
Ghizlane Maarifi ◽  
Sophie-Marie Aicher ◽  
Nathalie Arhel ◽  
Artem Baidaliuk ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Nuclear Bodies ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Dna Viruses ◽  
Over Expression ◽  
Interferon Stimulated Genes ◽  
Basal Expression ◽  
Pml Nuclear Bodies ◽  
Antiviral Activities

While interferon restricts SARS-CoV-2 replication in cell culture, only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 replication in human cells. Basal expression of DAXX was sufficient to limit the replication of the virus, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites of viral replication and led to its degradation. Together, these results demonstrate that DAXX is a potent restriction factor for SARS-CoV-2 and that the virus has evolved a mechanism to counteract its action.

scholarly journals Mitochondrial Antiviral Signaling Protein Plays a Major Role in Induction of the Fish Innate Immune Response against RNA and DNA Viruses

2009 ◽  
Vol 83 (16) ◽  
pp. 7815-7827 ◽  
Author(s):  
Stéphane Biacchesi ◽  
Monique LeBerre ◽  
Annie Lamoureux ◽  
Yoann Louise ◽  
Emilie Lauret ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Teleost Fish ◽  
Rna Virus ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Fish Cells ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Viral infection triggers host innate immune responses through cellular sensor molecules which activate multiple signaling cascades that induce the production of interferons (IFN) and other cytokines. The recent identification of mammalian cytoplasmic viral RNA sensors, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and their mitochondrial adaptor, the mitochondrial antiviral signaling protein (MAVS), also called IPS-1, VISA, and Cardif, highlights the significance of these molecules in the induction of IFN. Teleost fish also possess a strong IFN system, but nothing is known concerning the RLRs and their downstream adaptor. In this study, we cloned MAVS cDNAs from several fish species (including salmon and zebrafish) and showed that they were orthologs of mammalian MAVS. We demonstrated that overexpression of these mitochondrial proteins in fish cells led to a constitutive induction of IFN and IFN-stimulated genes (ISGs). MAVS-overexpressing cells were almost fully protected against RNA virus infection, with a strong inhibition of both DNA and RNA virus replication (1,000- and 10,000-fold decreases, respectively). Analyses of MAVS deletion mutants showed that both the N-terminal CARD-like and C-terminal transmembrane domains, but not the central proline-rich region, were indispensable for MAVS signaling function. In addition, we cloned the cDNAs encoding a RIG-I-like molecule from salmonid and cyprinid cell lines. Like the case with MAVS, overexpression of RIG-I CARDs in fish cells led to a strong induction of both IFN and ISGs, conferring on fish cells full protection against RNA virus infection. This report provides the first demonstration that teleost fish possess a functional RLR pathway in which MAVS may play a central role in the induction of the innate immune response.

scholarly journals Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junji Xing ◽  
Ao Zhang ◽  
Yong Du ◽  
Mingli Fang ◽  
Laurie J. Minze ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protective Immunity ◽  
Viral Infections ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Mitochondrial Antiviral Signaling ◽  
Phosphoinositide 3 Kinase

AbstractInnate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.

scholarly journals Type III interferons disrupt the lung epithelial barrier upon viral recognition

2020 ◽  
Author(s):  
Achille Broggi ◽  
Sreya Ghosh ◽  
Benedetta Sposito ◽  
Roberto Spreafico ◽  
Fabio Balzarini ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Rna Virus ◽  
Virus Infections ◽  
Highly Pathogenic ◽  
Type Iii ◽  
Lung Epithelial ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Viral Recognition

AbstractLower respiratory tract infections are a leading cause of mortality driven by infectious agents. RNA viruses such as influenza virus, respiratory syncytial virus and the new pandemic coronavirus SARS-CoV-2 can be highly pathogenic. Clinical and experimental evidence indicate that most severe and lethal cases do not depend on the viral burden and are, instead, characterized by an aberrant immune response. In this work we assessed how the innate immune response contributes to the pathogenesis of RNA virus infections. We demonstrate that type III interferons produced by dendritic cells in the lung in response to viral recognition cause barrier damage and compromise the host tissue tolerance. In particular, type III interferons inhibit tissue repair and lung epithelial cell proliferation, causing susceptibility to lethal bacterial superinfections. Overall, our data give a strong mandate to rethink the pathophysiological roles of this group of interferons and their possible use in the clinical practice against endemic as well as emerging viral infections.

scholarly journals DNA-PK is a DNA sensor for IRF-3-dependent innate immunity

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Brian J Ferguson ◽  
Daniel S Mansur ◽  
Nicholas E Peters ◽  
Hongwei Ren ◽  
Geoffrey L Smith
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Vaccine Development ◽  
Rna Virus ◽  
Severe Combined Immunodeficiency ◽  
Type I ◽  
Dna Sensor ◽  
Dna Viruses ◽  
Cytoplasmic Dna ◽  
Dependent Protein

Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity.

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