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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / metabolism*
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Amino Acid Sequence
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Animals
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Antigens, Differentiation / metabolism*
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Cell Line
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Gene Expression Regulation, Viral / genetics
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Gene Expression Regulation, Viral / physiology
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Humans
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Interferon Regulatory Factor-3
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Interferon-beta / biosynthesis
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Lymphocyte Activation / genetics
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Lymphocyte Activation / physiology
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / physiology*
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Membrane Glycoproteins / metabolism*
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Mice
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Molecular Sequence Data
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Myeloid Differentiation Factor 88
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Periplasmic Binding Proteins
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Protein Structure, Tertiary / genetics
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Protein Structure, Tertiary / physiology
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism*
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T-Lymphocytes / physiology
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factors / metabolism
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Vaccinia virus / genetics
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Vaccinia virus / metabolism*
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Vaccinia virus / pathogenicity
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Viral Proteins / genetics
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Viral Proteins / metabolism*
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Virus Diseases / genetics
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Virus Diseases / physiopathology
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Virus Replication / genetics
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Virus Replication / physiology
Substances
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A46R protein, vaccinia virus
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A52R protein, vaccinia virus
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ATP-Binding Cassette Transporters
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Differentiation
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DNA-Binding Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Periplasmic Binding Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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TICAM1 protein, human
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TLR3 protein, human
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TLR4 protein, human
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factors
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TroA protein, Treponema pallidum
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Viral Proteins
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Interferon-beta