A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling

Poxviruses employ many strategies to evade and neutralize the host immune r esponse. In this study, we have identified two vaccinia virus ORFs, termed A46R and A52R, that share amino acid sequence similarity with the Toll/IL-1 receptor (TIR) domain, a motif that defines the IL-1/Toll-like receptor (T LR) superfamily of receptors, which have a key role in innate immunity and inflammation. When expressed in mammalian cells, the protein products of bo th ORFs were shown to interfere specifically with IL-1 signal transduction. A46R partially inhibited IL-1-mediated activation of the transcription fac tor NF kappa B, and A52R potently blocked both IL-1- and TLR4-mediated NF k appa B activation. MyD88 is a TIR domain-containing adapter molecule known to have a central role in both IL-1 and TLR4 signaling. A52R mimicked the d ominant-negative effect of a truncated version of MyD88 on IL-1, TLR4, and IL-18 signaling but had no effect on MyD88-independent signaling pathways. Therefore, A46R and A52R are likely to represent a mechanism used by vaccin ia virus of suppressing TIR domain-dependent intracellular-signaling.