Viral immune evasion: HSV-1 immediate early protein ICP0 inhibits TLR2-driven NF-kB activation (94.18)

Abstract

Abstract The recognition of Pathogen Associated Molecular Patterns (PAMPS) by conserved receptors of the innate immune system is a critical step in the development of anti-viral immunity. We have studied a class of innate immune receptors, the Toll-like receptors (TLRs), in the anti-viral response to viruses including Herpesviruses. We have previously shown that HSV-1 infection induces NF-kB dependent innate immune responses via TLR2. TLR2 activation by HSV-1 drives NF-kB-dependent inflammatory cytokine production which plays a critical role in the HSV-1 pathology particularly the development of lethal encephalitis. Here we describe studies of TLR2-HSV-1 interaction which reveal a complex interplay between viral gene products and the host innate immune response. Using various mutant HSV-1 viruses, we find that ICP0, an immediate early viral protein, significantly inhibited TLR2-driven responses. Further, ICP0 expression alone was sufficient to block TLR2 activation by both viral and non-viral stimuli. Expression of ICP0 reduced levels of MyD88 and Mal, two critical adaptors for TLR2 signaling. ICP0 did not affect TRIF- or TRAM-driven NF-kB, but did block MyD88- and Mal-driven NF-kB responses. Proteosomes were required to inhibit TLR2 activation as was the E3 ligase function of ICP0. Our results suggest that ICP0 promotes degradation of the TLR adapter proteins, MyD88 and Mal, thereby blocking TLR2-driven activation of NF-kB sensitive inflammatory target genes.