Toll‐like receptor 3 in viral pathogenesis: friend or foe?

Summary Viral infections frequently induce acute and chronic inflammatory diseases, yet the contribution of the innate immune response to a detrimental host response remains poorly understood. In virus‐infected cells, double‐stranded RNA (ds RNA ) is generated as an intermediate during viral replication. Cell necrosis (and the release of endogenous ds RNA ) is a common event during both sterile and infectious inflammatory processes. The discovery of Toll‐like receptor 3 ( TLR 3) as an interferon‐inducing ds RNA sensor led to the assumption that TLR 3 was the master sentinel against viral infections. This simplistic view has been challenged by the discovery of at least three members of the DE xd/ H ‐box helicase cytosolic sensors of ds RNA that share with TLR 3 the Toll–interleukin‐1 receptor ( TIR ) ‐adapter molecule TIR domain‐containing adaptor protein interferon‐β ( TRIF ) for downstream type I interferon signalling. Data are conflicting on the role of TLR 3 in protective immunity against viruses in the mouse model. Varying susceptibility to infection and disease outcomes have been reported in TLR 3‐immunodeficient mice. Surprisingly, the susceptibility to develop herpes simplex virus‐1 encephalitis in humans with inborn defects of the TLR 3 pathway varies, and TLR 3‐deficient humans do not show increased susceptibility to other viral infections. Therefore, a current challenge is to understand the protective versus pathogenic contribution of TLR 3 in viral infections. We review recent advances in the identification of TLR 3‐signalling pathways, endogenous and virus‐induced negative regulators of the TLR 3 cascade, and discuss the protective versus pathogenic role of TLR 3 in viral pathogenesis.