Antiviral Actions of Interferons
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TLDR
Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs.Abstract:
Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.read more
Citations
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Journal ArticleDOI
The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.
Mitsutoshi Yoneyama,Mika Kikuchi,Takashi Natsukawa,Noriaki Shinobu,Tadaatsu Imaizumi,Makoto Miyagishi,Kazunari Taira,Shizuo Akira,Takashi Fujita +8 more
TL;DR: In this article, the authors identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling.
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IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.
Sergei V. Kotenko,Grant Gallagher,Vitaliy V. Baurin,Anita Lewis-Antes,Meiling Shen,Nital K. Shah,Jerome A. Langer,Faruk Sheikh,Harold Dickensheets,Raymond P. Donnelly +9 more
TL;DR: The identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state and may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.
Journal ArticleDOI
Shared and Unique Functions of the DExD/H-Box Helicases RIG-I, MDA5, and LGP2 in Antiviral Innate Immunity
Mitsutoshi Yoneyama,Mika Kikuchi,Kanae Matsumoto,Tadaatsu Imaizumi,Makoto Miyagishi,Makoto Miyagishi,Kazunari Taira,Kazunari Taira,Eileen Foy,Yueh Ming Loo,Michael Gale,Shizuo Akira,Shin Yonehara,Atsushi Kato,Takashi Fujita +14 more
TL;DR: The results highlight ingenious mechanisms for initiating antiviral innate immune responses and the action of virus-encoded inhibitors.
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Triggering the Interferon Antiviral Response Through an IKK-Related Pathway
Sonia Sharma,Benjamin R. tenOever,Nathalie Grandvaux,Guo-Ping Zhou,Rongtuan Lin,John Hiscott +5 more
TL;DR: It is reported here that the IκB kinase (IKK)–related kinases IKKϵ and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRf-3 and IRF-7.
Journal ArticleDOI
Viruses and interferon: a fight for supremacy
TL;DR: The interplay between the IFN system and four medically important and challenging viruses — influenza, hepatitis C, herpes simplex and vaccinia — is discussed to highlight the diversity of viral strategies.
References
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Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
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Nitric oxide and macrophage function
TL;DR: Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
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How cells respond to interferons
TL;DR: The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interFERons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.
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STATs and Gene Regulation
TL;DR: The discovery of a STAT in Drosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins.
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Interferon Alfa-2b Alone or in Combination with Ribavirin as Initial Treatment for Chronic Hepatitis C
John G. McHutchison,Stuart C. Gordon,Eugene R. Schiff,Mitchell L. Shiffman,William M. Lee,Vinod K. Rustgi,Zachary Goodman,Mei Hsiu Ling,Susannah Cort,Janice K. Albrecht +9 more
TL;DR: In patients with chronic hepatitis C, initial therapy withinterferon and ribavirin was more effective than treatment with interferon alone.