title: Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence.
abstract: Viral 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.
authors.affiliation: Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Julianne
authors.initials: J
authors.lastname: Stack
authors.forename: Ismar R
authors.initials: IR
authors.lastname: Haga
authors.forename: Martina
authors.initials: M
authors.lastname: Schröder
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: Geraldine
authors.initials: G
authors.lastname: Maloney
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reading
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
mesh_terms: D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D033902:Periplasmic Binding Proteins; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014777:Virus Diseases / Q000235:genetics / Q000503:physiopathology; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
chemical_list: C413651:A46R protein, vaccinia virus; C413650:A52R protein, vaccinia virus; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D033902:Periplasmic Binding Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; C120377:TroA protein, Treponema pallidum; D014764:Viral Proteins; D016899:Interferon-beta