Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence
Department of Medicine, Division of Infectious Diseases and Immunology
ATP-Binding Cassette Transporters; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Amino Acid Sequence; Animals; Antigens, Differentiation; Cell Line; DNA-Binding Proteins; Disease Models, Animal; Gene Expression Regulation, Viral; Humans; Interferon Regulatory Factor-3; Interferon-beta; Lymphocyte Activation; MAP Kinase Signaling System; Membrane Glycoproteins; Mice; Molecular Sequence Data; Myeloid Differentiation Factor 88; Periplasmic Binding Proteins; Protein Structure, Tertiary; Receptors, Cell Surface; Receptors, Immunologic; T-Lymphocytes; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptors; Transcription Factors; Vaccinia virus; Viral Proteins; Virus Diseases; Virus Replication
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.
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Citation: J Exp Med. 2005 Mar 21;201(6):1007-18. Epub 2005 Mar 14. Link to article on publisher's site