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dc.contributor.creatorStack, Julianne
dc.contributor.creatorHaga, Ismar R.
dc.contributor.creatorSchröder, Martina
dc.contributor.creatorBartlett, Nathan W.
dc.contributor.creatorMaloney, Geraldine
dc.contributor.creatorReading, Patrick C.
dc.contributor.creatorFitzgerald, Katherine A.
dc.contributor.creatorSmith, Geoffrey L.
dc.contributor.creatorBowie, Andrew G.
dc.date.accessioned2019-02-26T12:49:38Z
dc.date.available2019-02-26T12:49:38Z
dc.date.issued2005
dc.identifier.citationStack, J. et al. (2005) Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence. J Exp Med. 201(6): 1007-18.en_US
dc.identifier.urihttp://hdl.handle.net/10395/2680
dc.descriptionVaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence.en_US
dc.description.abstractViral 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- (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor B. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN- 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_US
dc.language.isoengen_US
dc.publisherThe Rockefeller University Pressen_US
dc.relation.ispartofseries201;6
dc.rights.uriwww.jem.org/cgi/doi/10.1084/jem.20041442en_US
dc.subjectVaccinia virus proteinen_US
dc.subjectA46Ren_US
dc.subjectToll-like–interleukin-1en_US
dc.subjectReceptor adaptorsen_US
dc.subjectVirulenceen_US
dc.titleVaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulenceen_US
dc.typeArticleen_US
dc.type.supercollectionall_mic_researchen_US
dc.type.supercollectionmic_published_revieweden_US
dc.description.versionYesen_US
dc.identifier.doi10.1084/jem.20041442


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