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Published online 14 March 2005 doi:10.1084/jem.20041442
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 1007-1018
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ARTICLE

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

Julianne Stack1, Ismar R. Haga2, Martina Schröder1, Nathan W. Bartlett2, Geraldine Maloney1, Patrick C. Reading2, Katherine A. Fitzgerald3, Geoffrey L. Smith2, and Andrew G. Bowie1

1 Department of Biochemistry, Trinity College, Dublin 2, Ireland
2 Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, London W2 1PG, England, UK
3 Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01604

CORRESPONDENCE Andrew Bowie: agbowie{at}tcd.ie

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

Abbreviations used: ERK, extracellular signal–regulated kinase; IRAK, IL-1 receptor–associated kinase; IRF3, interferon regulatory factor 3; JNK, c-Jun NH2-terminal protein kinase; Mal, MyD88 adaptor-like; MOI, multiplicity of infection; MyD88, myeloid differentiation factor 88; PAM, pathogen-associated molecule; RANTES, regulated on activation, normal T cell expressed and secreted; SARM, sterile {alpha} and HEAT/Armadillo motifs-containing protein; TIR, Toll–IL-1 resistance; TLR, Toll-like receptors; TRAF, TNF receptor–associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing IFN-ß; VV, vaccinia virus.

J. Stack and I.R. Haga contributed equally to this work.

I.R. Haga's present address is Department of Biochemistry, Trinity College, Dublin 2, Ireland.

P.C. Reading's present address is Department of Microbiology and Immunology, University of Melbourne, Victoria, 3010, Australia.


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