Retinoic Acid-inducible Gene-I and Interferon-β Promoter Stimulator-1 Augment Proapoptotic Responses Following Mammalian Reovirus Infection via Interferon Regulatory Factor-3

During viral infection, cells initiate antiviral responses to contain replication and inhibit virus spread. One protective mechanism involves activation of transcription factors interferon regulatory factor-3 (IRF-3) and NF-κB, resulting in secretion of the antiviral cytokine, interferon-β. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon-β and apoptosis, raising the possibility that both pathways are initiated by a common cellular sensor. We show here that reovirus activates IRF-3 with kinetics that parallel the activation of NF-κB, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon-β promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-κB. Interferon-β promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response. During viral infection, cells initiate antiviral responses to contain replication and inhibit virus spread. One protective mechanism involves activation of transcription factors interferon regulatory factor-3 (IRF-3) and NF-κB, resulting in secretion of the antiviral cytokine, interferon-β. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon-β and apoptosis, raising the possibility that both pathways are initiated by a common cellular sensor. We show here that reovirus activates IRF-3 with kinetics that parallel the activation of NF-κB, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon-β promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-κB. Interferon-β promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response. A primary function of the innate immune system is to detect nascent viral infections and direct subsequent cellular responses. The innate immune system responds to infection by producing a range of soluble cytokines, such as interferon-β (IFN-β), 5The abbreviations used are: IFN, interferon; TLR, Toll-like receptor; RIG-I, retinoic acid inducible gene-I; Mda-5, melanoma differentiation-associated protein-5; IPS-1, interferon-β promoter stimulator-1; IKK, inhibitor of κB kinase; IRF-3, interferon regulatory factor-3; ISG, interferon-stimulated gene; PKR, protein kinase R; ds, double-stranded; MEF, mouse embryo fibroblast; T3D, type 3 Dearing; ISVP, infectious subvirion particle; STAT, signal transducers and activators of transcription; MOI, muliplicity of infection; PFU, plaque-forming unit(s); PBS, phosphate-buffered saline; RT, reverse transcription; siRNA, small interfering RNA. that create an antiviral state in surrounding tissue. In response to these immune pressures, viruses have evolved multiple strategies for subverting innate immunity, which frequently center on manipulating cell death pathways. The interface between the innate immune response, viral infection, and the cellular apoptotic machinery is therefore a critical nexus of disease pathogenesis. Cells possess a variety of sensors to detect invading pathogens. Toll-like receptors (TLRs) and other pattern recognition receptors, including the nucleotide-binding oligomerization domain proteins and RNA helicases such as retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein-5 (Mda-5), recognize viral pathogen-associated molecular patterns (1Mogensen T.H. Paludan S.R. J. Mol. Med. 2005; 83: 180-192Crossref PubMed Scopus (106) Google Scholar). TLRs are expressed on the cell surface and recognize extracellular pathogen-associated molecular patterns, whereas RIG-I and Mda-5 detect intracellular viral RNA products (2Sumpter R.J. Loo Y.M. Foy E. Li K. Yoneyama M. Fujita T. Lemon S.M. Gale M.J. J. Virol. 2005; 79: 2689-2699Crossref PubMed Scopus (734) Google Scholar, 3Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3136) Google Scholar, 4Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. Yamaguchi O. Otsu K. Tsujimura T. Koh C.S. Reis e Sousa C. Matsuura Y. Fujita T. Akira S. Nature. 2006; 441: 101-105Crossref PubMed Scopus (2933) Google Scholar). RIG-I recognizes viral RNAs from the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae families, whereas Mda-5 is involved in the response to Picornaviridae (4Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. Yamaguchi O. Otsu K. Tsujimura T. Koh C.S. Reis e Sousa C. Matsuura Y. Fujita T. Akira S. Nature. 2006; 441: 101-105Crossref PubMed Scopus (2933) Google Scholar). The ligand for RIG-I has been identified asa5′ triphosphate moiety on single- or double-stranded RNA (5Hornung V. Ellegast J. Kim S. Brzozka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. Endres S. Hartmann G. Science. 2006; 314: 994-997Crossref PubMed Scopus (1909) Google Scholar, 6Pichlmair A. Schulz O. Tan C.P. Naslund T.I. Liljestrom P. Weber F. Reis e Sousa C. Science. 2006; 314: 997-1001Crossref PubMed Scopus (1779) Google Scholar); the molecular ligand for Mda-5 is unknown. Following ligand engagement, these intracellular sensors signal through caspase activation and recruitment domains to activate the adaptor, interferon-β promoter stimulator-1 (IPS-1/MAVS/VISA/Cardif) (7Kawai T. Takahashi K. Sato S. Coban C. Kumar H. Kato H. Ishii K.J. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 981-988Crossref PubMed Scopus (2032) Google Scholar, 8Seth R.B. Sun L. Ea C.K. Chen Z.J. Cell. 2005; 122: 669-682Abstract Full Text Full Text PDF PubMed Scopus (2518) Google Scholar, 9Xu L.G. Wang Y.Y. Han K.J. Li L.Y. Zhai Z. Shu H.B. Mol. Cell. 2005; 19: 727-740Abstract Full Text Full Text PDF PubMed Scopus (1518) Google Scholar, 10Meylan E. Curran J. Hofmann K. Moradpour D. Binder M. Bartenschlager R. Tschopp J. Nature. 2005; 437: 1167-1172Crossref PubMed Scopus (1973) Google Scholar). IPS-1 activates inhibitor of κB kinase (IKK)-α, IKK-β, IKK-ϵ, and Tank-binding kinase 1 to phosphorylate transcription factors, including activating transcription factor-2/c-Jun, NF-κB, and interferon regulatory factor-3 (IRF-3), which direct transcription of antiviral genes. The main cytokine effectors of the innate antiviral response are type I interferons IFN-α and IFN-β, which are secreted from cells and act in an autocrine or paracrine manner via binding to a common IFN-α/β receptor (11Chawla-Sarkar M. Lindner D.J. Liu Y.F. Williams B.R. Sen G.C. Silverman R.H. Borden E.C. Apoptosis. 2003; 8: 237-249Crossref PubMed Scopus (677) Google Scholar). Receptor engagement activates the JAK/STAT signaling pathway, which initiates a second transcriptional response to induce IFN-stimulated genes (ISGs), which directly mediate antiviral effects. One such ISG is IRF-7, which enhances IFN production (12Lu R. Au W.C. Yeow W.S. Hageman N. Pitha P.M. J. Biol. Chem. 2000; 275: 31805-31812Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Other ISGs, such as 2′,5′-oligoadenylate synthase, RNase L, and protein kinase R (PKR), inhibit cellular protein synthesis to prevent viral replication (11Chawla-Sarkar M. Lindner D.J. Liu Y.F. Williams B.R. Sen G.C. Silverman R.H. Borden E.C. Apoptosis. 2003; 8: 237-249Crossref PubMed Scopus (677) Google Scholar). Innate antiviral responses interface both directly and indirectly with the cellular apoptosis machinery. Type I IFNs mediate proapoptotic responses, as several ISGs have ascribed functions in both extrinsic and intrinsic pathways of apoptosis (11Chawla-Sarkar M. Lindner D.J. Liu Y.F. Williams B.R. Sen G.C. Silverman R.H. Borden E.C. Apoptosis. 2003; 8: 237-249Crossref PubMed Scopus (677) Google Scholar). Proapoptotic ISGs include tumor necrosis factor-related apoptosis-inducing ligand (13Kayagaki N. Yamaguchi N. Nakayama M. Eto H. Okumura K. Yagita H. J. of Exp. Med. 1999; 189: 1451-1460Crossref PubMed Scopus (435) Google Scholar) and Fas (14Selleri C. Sato T. Del Vecchio L. Luciano L. Barrett A.J. Rotoli B. Young N.S. Maciejewski J.P. Blood. 1997; PubMed Google Scholar). these cell or (11Chawla-Sarkar M. Lindner D.J. Liu Y.F. Williams B.R. Sen G.C. Silverman R.H. Borden E.C. Apoptosis. 2003; 8: 237-249Crossref PubMed Scopus (677) Google Scholar). Innate immune signaling induce apoptotic cell death in an IPS-1 to the of suggesting that the antiviral response with or R.B. Sun L. Ea C.K. Chen Z.J. Cell. 2005; 122: 669-682Abstract Full Text Full Text PDF PubMed Scopus (2518) Google Scholar). IPS-1 with via death domain to mediate activation (7Kawai T. Takahashi K. Sato S. Coban C. Kumar H. Kato H. Ishii K.J. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 981-988Crossref PubMed Scopus (2032) Google suggesting that via death domain activation of RIG-I and Mda-5 to extrinsic apoptotic pathways. activation of IRF-3 directly induce apoptosis via a mechanism of induction of IFN C. S. M.J. C. R. J. J. Virol. 2000; PubMed Scopus Google Scholar). are the cellular apoptotic response. Mammalian are viruses with a of of double-stranded RNA P.M. Williams Scholar). Following infection of reovirus to the and P.M. Williams Scholar). by reovirus is the primary mechanism for S.M. J. Virol. 1997; PubMed Google Scholar) and R. C. B. K. J. Virol. PubMed Scopus Google Scholar). an regulatory in apoptosis by reovirus in cells P. J. Virol. 2000; PubMed Scopus Google Scholar) and in S.M. M.J. Han T. B. J. 2005; PubMed Scopus Google Scholar). induces in cells and in In the is protective S.M. M.J. Han T. B. J. 2005; PubMed Scopus Google and reovirus induction of and to in with the of a to S.M. M.J. Han T. B. J. 2005; PubMed Scopus Google Scholar, B. J. J. Virol. PubMed Google Scholar). by reovirus in and M.J. K. B. J. Virol. 2005; 79: PubMed Scopus Google suggesting that of reovirus-induced production are cell IRF-3 is required for induction following reovirus infection of B. J. Virol. 1999; PubMed Google Scholar). of reovirus-induced IRF-3 activation are unknown. of reovirus-induced IFN production and the interface between these pathways and apoptosis, to the viral and cellular of IFN production following reovirus infection and the functional of these pathways in reovirus replication and apoptosis The that reovirus activates IRF-3 via a mechanism on in viral RIG-I, and In RIG-I and IPS-1 are dispensable for reovirus-induced activation of NF-κB. IRF-3 reovirus in in of production of type 1 IRF-3 and IPS-1 are required for efficient induction of apoptosis following reovirus that RIG-I and IPS-1 are involved in cell death signaling responses to viral infection and a functional between innate immune activation and apoptosis. and and mouse embryo in to contain of and of cells in to contain of and of B. in IRF-3 M. H. N. M. K. K. T. M. S. N. T. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) from type 3 is a by and is to with the of a acid in the protein to and therefore of infectious subvirion with to that of T. P. S. Full Text Full Text PDF PubMed Scopus Google Scholar). reovirus second or of reovirus as J. Virol. PubMed Google Scholar). from cell and for to and PubMed Scopus Google Scholar) and in of reovirus in from an of 1 PubMed Scopus Google Scholar). by cells R. J. Virol. PubMed Google Scholar). as J. Virol. PubMed Scopus Google Scholar) and by and for IRF-3 and from from M. Y. Sato M. K. Fujita T. 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Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3136) Google Scholar, T. Takahashi K. Sato S. Coban C. Kumar H. Kato H. Ishii K.J. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 981-988Crossref PubMed Scopus (2032) Google Scholar). a signaling RIG-I and IPS-1 is required for activation by for the to following reovirus of RIG-I activation following reovirus infection in to IRF-3 reovirus-induced and activation by but that by tumor necrosis In with these an for RIG-I or IPS-1 on activation by reovirus and but an for IPS-1 activation by an reovirus-induced activation by a of in the or of IPS-1 that reovirus activates via a mechanism that is of RIG-I and We to the functional of IRF-3 activation on reovirus these used from in IRF-3 M. H. N. M. K. K. T. M. S. N. T. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We reovirus a of viral replication following infection an of and as by on of or following in IRF-3 or IRF-3 IRF-3 activation has on reovirus a replication IRF-3 the of reovirus to in cell multiple of infection, IRF-3 and IRF-3 an of 1 and a of and reovirus in IRF-3 in with following infection of IRF-3 IRF-3 the of reovirus to to cells in an the to IFN is with IFN by in of IRF-3 and IRF-3 following IRF-3 required for production of IFN-α and following reovirus infection A and that the in IFN production for the in virus in IRF-3 IRF-3 with and with in the in IRF-3 with reovirus and and of interferon reovirus in IRF-3 to to in IRF-3 suggesting that the of reovirus by IRF-3 is by the production of type 1 The IFN has been in the of reovirus to induce apoptosis in cell S.M. B. M.J. J. Virol. 2006; PubMed Scopus Google Scholar) and in S.M. M.J. Han T. B. J. 2005; PubMed Scopus Google Scholar). the of IRF-3 in reovirus-induced apoptosis, the of reovirus to induce apoptosis in IRF-3 and IRF-3 In with IRF-3 reovirus of apoptosis in IRF-3 as by in cell and of cells the of the signaling in apoptosis by the of reovirus to induce activation in cells with for by reovirus infection in cells with an IPS-1 in with with a signaling by reovirus infection is by IPS-1 and Innate immune of viral infection initiates signaling pathways that viral replication and viral that viral initiates cellular responses via RIG-I, IPS-1, and IRF-3, which function to reovirus-induced apoptosis. that RIG-I is the primary of reovirus infection in cells and The efficient of by RIG-I that Mda-5 for RIG-I in of reovirus infection in these the IFN response to reovirus is in cells and from Mda-5 L. S. M. B. R. M. M. S. A. 2006; PubMed Scopus Google Scholar). is that other sensors function to recognize reovirus in cell reovirus induces IFN in cells R. B. and M. 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PubMed Scopus Google suggesting that the as the reovirus RIG-I synthesis is to PubMed Scopus Google suggesting that RNAs have to the by is that of reovirus in to of the viral and of both and the of reovirus enhances IFN suggesting that the PubMed Scopus Google Scholar). small RNA with reovirus S. A. PubMed Scopus Google Scholar) the following viral with Other cellular including L. R. Nature. PubMed Scopus Google Scholar) and E. K. J. N.S. Williams B.R. Cell. Full Text PDF PubMed Scopus Google to and function in antiviral signaling pathways initiated in response to reovirus is expressed by cells M. D. N. G. A. R. C. G. P. A. J. Immunol. 2000; PubMed Scopus Google a variety of cells E. 2000; PubMed Scopus Google and and in the system M. R. D. J. Exp. PubMed Scopus Google Scholar). to that is from the extracellular L. R. Nature. PubMed Scopus Google Scholar). used in including M. K. M. H. M. Y. Yamamoto A. T. J. 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PubMed Scopus Google in to the activation of which requires and Y. M. T. M. R. M. J. Exp. Med. 1999; 189: PubMed Scopus Google Scholar). The signal transducers that reovirus to the are engagement of RIG-I and IPS-1 activates by M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3136) Google Scholar, T. Takahashi K. Sato S. Coban C. Kumar H. Kato H. Ishii K.J. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: 981-988Crossref PubMed Scopus (2032) Google that reovirus activates of RIG-I and The reovirus protein is to induce apoptosis expressed in cell A. Kim K. J. Virol. 2006; PubMed Scopus Google in reovirus-induced We that a cellular kinase that activates or the directly to mediate are in to by which reovirus activates NF-κB. of IRF-3, in to NF-κB, as signaling in the cell death response to reovirus infection several by which these proteins direct an apoptotic One possibility is that these are by the production of type I IRF-3 and NF-κB, with activating transcription factor-2/c-Jun, the promoter and production (1Mogensen T.H. Paludan S.R. J. Mol. Med. 2005; 83: 180-192Crossref PubMed Scopus (106) Google Scholar). Type I IFNs proapoptotic via the induction of proteins such as Fas and 2′,5′-oligoadenylate synthase, which direct apoptotic signaling (14Selleri C. Sato T. Del Vecchio L. Luciano L. Barrett A.J. Rotoli B. Young N.S. Maciejewski J.P. Blood. 1997; PubMed Google Scholar, Li K. R.J. J. Exp. Med. 1997; PubMed Scopus Google Scholar). production in response to reovirus infection a protective in in and in by viral replication S.M. M.J. 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G. and R. for and with

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