Title
Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Publication Date
2005-03-16
Document Type
Article
Subjects
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
Disciplines
Immunology and Infectious Disease
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.
DOI of Published Version
10.1084/jem.20041442
Source
J Exp Med. 2005 Mar 21;201(6):1007-18. Epub 2005 Mar 14. Link to article on publisher's site
Journal/Book/Conference Title
The Journal of experimental medicine
Related Resources
PubMed ID
15767367
Repository Citation
Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading P, Fitzgerald KA, Smith GL, Bowie AG. (2005). Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. Infectious Diseases and Immunology Publications. https://doi.org/10.1084/jem.20041442. Retrieved from https://escholarship.umassmed.edu/infdis_pp/88