Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence

Julianne Stack, Ismar R Haga, Martina Schröder, Nathan W Bartlett, Geraldine Maloney, Patrick C Reading, Katherine A Fitzgerald, Geoffrey L Smith, Andrew G Bowie

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1007-18
Number of pages12
JournalJournal of Experimental Medicine
Volume201
Issue number6
DOIs
Publication statusPublished - 21 Mar 2005

Keywords

  • 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

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