Stack, JulianneHaga, Ismar R.Schroder, MartinaBartlett, Nathan W.Maloney, GeraldineReading, PatrickFitzgerald, Katherine ASmith, Geoffrey L.Bowie, Andrew G.2022-08-232022-08-232005-03-162011-03-25J Exp Med. 2005 Mar 21;201(6):1007-18. Epub 2005 Mar 14. <a href="http://dx.doi.org/10.1084/jem.20041442">Link to article on publisher's site</a>0022-1007 (Linking)10.1084/jem.2004144215767367https://hdl.handle.net/20.500.14038/35254Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like-interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain-containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain-containing adaptor inducing IFN-beta (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor kappaB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-beta by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.en-USATP-Binding Cassette TransportersAdaptor Proteins, Signal TransducingAdaptor Proteins, Vesicular TransportAmino Acid SequenceAnimalsAntigens, DifferentiationCell LineDNA-Binding ProteinsDisease Models, AnimalGene Expression Regulation, ViralHumansInterferon Regulatory Factor-3Interferon-betaLymphocyte ActivationMAP Kinase Signaling SystemMembrane GlycoproteinsMiceMolecular Sequence DataMyeloid Differentiation Factor 88Periplasmic Binding ProteinsProtein Structure, TertiaryReceptors, Cell SurfaceReceptors, ImmunologicT-LymphocytesToll-Like Receptor 3Toll-Like Receptor 4Toll-Like ReceptorsTranscription FactorsVaccinia virusViral ProteinsVirus DiseasesVirus ReplicationImmunology and Infectious DiseaseJournal Articlehttps://escholarship.umassmed.edu/infdis_pp/881901411infdis_pp/88