Stack, Julianne and Haga, Ismar R. and Schroeder, Martina and Bartlett, Nathan W. and Maloney, Geraldine and Reading, Patrick C. and Fitzgerald, Katherine A. and Smith, Geoffrey L. and Bowie, Andrew G. (2005) Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence. Journal of Experimental Medicine, 201 (6). pp. 1007-1018. ISSN 0022-1007

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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-β (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor κB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN- β 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.

Item Type:	Article
Keywords:	Vaccinia virus; protein A46R; Toll-like–interleukin-1; receptor adaptors; virulence;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12664
Identification Number:	https://doi.org/10.1084/jem.20041442
Depositing User:	Martina Schroeder
Date Deposited:	31 Mar 2020 12:33
Journal or Publication Title:	Journal of Experimental Medicine
Publisher:	Rockefeller University Press
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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