title: The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense.
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 kappa B (NF-kappa B) 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.
authors.affiliation: The Cytokine Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Harte
authors.forename: Ismar R
authors.initials: IR
authors.lastname: Haga
authors.forename: Geraldine
authors.initials: G
authors.lastname: Maloney
authors.forename: Pearl
authors.initials: P
authors.lastname: Gray
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reading
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Andrew
authors.initials: A
authors.lastname: Bowie
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins; D005260:Female; D017353:Gene Deletion; D005814:Genes, Viral; D006801:Humans; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014774:Virulence
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; C495344:TLR3 protein, human; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014764:Viral Proteins; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases