Journal
PLOS PATHOGENS
Volume 9, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1003514
Keywords
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Funding
- BayGene (Bayerisches Staatsministerium fur Wissenschaft, Forschung und Kunst JH)
- DFG [SFB 576]
- MRC [G0501453]
- BBSRC [BB/D019621/1]
- Scottish Enterprise
- Wellcome Trust [WT086403MA, WT066784]
- European Union (AntiPathoGN)
- BBSRC [BB/D019621/1, BBS/E/I/00001735] Funding Source: UKRI
- MRC [MC_UP_A550_1030, G0501453, MR/J002232/1, MC_UU_12014/5] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D019621/1, BBS/E/I/00001735] Funding Source: researchfish
- Medical Research Council [MC_UU_12014/5, MR/J002232/1, MC_UP_A550_1030, G0501453] Funding Source: researchfish
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Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-lambda) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-lambda induction suggests this is the major transcription factor for IFN-lambda expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-lambda secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-lambda 3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-lambda, provides evidence for the crucial role of IFN-lambda in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.
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