Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence
Citation:
Stack, J. Haga, I.R., Schroeder, M., Bartlett, N.W., Maloney, G., Reading, P.C., Fitzgerald, K.A., Smith, G.L. & Bowie, A.G, Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence, The Journal of Experimental Medicine, 201, 6, 2005, 1007 - 1018Download Item:
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-? (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor ?B. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-? 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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Higher Education Authority (HEA)
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http://people.tcd.ie/agbowieDescription:
PUBLISHEDPMID: 15767367
Author: BOWIE, ANDREW
Type of material:
Journal ArticleCollections
Series/Report no:
The Journal of Experimental Medicine201
6
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Full text availableKeywords:
Immunology, Toll-like receptorsSubject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1084/jem.20041442Metadata
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