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The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense

The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor κB (NF-κB) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor–associated kinase 2 (IRAK2) and tumor necrosis factor receptor–associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response. nuclear factor κB signal transduction vaccinia virus immunomodulation Toll-like receptor Footnotes ↵ * Abbreviations used in this paper: dsRNA, double-stranded RNA; IP, immunoprecipitation; IRAK, IL-1 receptor–associated kinase; Mal, MyD88 adaptor-like; NF, nuclear factor; TAB, TAK1 binding protein; TAK1, TGF-β–activated kinase 1; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRAF, TNF receptor associated factor; VV, vaccinia virus. A. Bowie and L. O'Neill contributed equally to the work. M. Harte's present address is Cancer Research Centre, Oncology Department, Queens University of Belfast, Belfast BT9 7AB, Northern Ireland. Submitted: 18 September 2002 Accepted: 17 December 2002 Revision received 8 November 2002 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense

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References (91)

Publisher
Rockefeller University Press
Copyright
© 2003 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20021652
Publisher site
See Article on Publisher Site

Abstract

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor κB (NF-κB) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor–associated kinase 2 (IRAK2) and tumor necrosis factor receptor–associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response. nuclear factor κB signal transduction vaccinia virus immunomodulation Toll-like receptor Footnotes ↵ * Abbreviations used in this paper: dsRNA, double-stranded RNA; IP, immunoprecipitation; IRAK, IL-1 receptor–associated kinase; Mal, MyD88 adaptor-like; NF, nuclear factor; TAB, TAK1 binding protein; TAK1, TGF-β–activated kinase 1; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRAF, TNF receptor associated factor; VV, vaccinia virus. A. Bowie and L. O'Neill contributed equally to the work. M. Harte's present address is Cancer Research Centre, Oncology Department, Queens University of Belfast, Belfast BT9 7AB, Northern Ireland. Submitted: 18 September 2002 Accepted: 17 December 2002 Revision received 8 November 2002

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Feb 3, 2003

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