Abstract
The discovery of the Toll-like receptors (TLRs) and their importance in the regulation of host responses to infection raised attention to the complex interplay between viral gene products and the host innate immune responses in determining the outcome of virus infection. Robust inflammatory cytokine responses are observed in herpes simplex virus (HSV)-infected animals and cells. Our studies have demonstrated that Toll-like receptor 2 (TLR2) activation by HSV results in NF-κB activation with concomitant inflammatory cytokine production and that TLR2 activation plays a critical role in HSV-induced pathology and mortality. Here we demonstrate that the HSV-1 immediate-early ICP0 protein reduces the TLR2-mediated inflammatory response to HSV 1 (HSV-1) infection. Expression of ICP0 alone is sufficient to block TLR2-driven responses to both viral and nonviral ligands at or downstream of the MyD88 adaptor and upstream of p65. ICP0 alone can also reduce the levels of MyD88 and Mal (TIRAP). In HSV-infected cells, the E3 ligase function of ICP0 and cellular proteasomal activity are required for the inhibitory activity. Our results argue for a model in which ICP0 promotes the degradation of TLR adaptor molecules and inhibition of the inflammatory response, much as it inhibits the interferon response by sequestration and degradation of interferon regulatory factor 3 (IRF-3).
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Cell Line
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Cytokines / biosynthesis
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Genes, Viral
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Herpesvirus 1, Human / genetics
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Herpesvirus 1, Human / pathogenicity
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Herpesvirus 1, Human / physiology*
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology
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Host-Pathogen Interactions / physiology
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / physiology*
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Inflammation Mediators / physiology
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Membrane Transport Proteins / physiology
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Mice
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Mice, Inbred C57BL
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Models, Biological
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Mutation
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Myelin Proteins / physiology
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88 / physiology
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NF-kappa B / physiology*
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Proteolipids / physiology
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Signal Transduction
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Toll-Like Receptor 2 / antagonists & inhibitors*
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / physiology
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / physiology*
Substances
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Cytokines
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Immediate-Early Proteins
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Inflammation Mediators
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MAL protein, human
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MYD88 protein, human
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Mal protein, mouse
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Membrane Transport Proteins
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Myelin Proteins
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proteolipids
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TLR2 protein, human
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Ubiquitin-Protein Ligases
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Vmw110 protein, Human herpesvirus 1