Abstract
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-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.
Highlights
Up to 90% of the global population is infected with the aherpesvirus Herpes simplex virus type I (HSV-1)
Co-infection with HSV-2 is a major contributor to Human Immunodeficiency Virus (HIV) transmission, so a better understanding of Herpes simplex virus type 1 (HSV-1)/HSV-2 disease has wide implications for global healthcare
Host factors (HFs) which positively or negatively regulate HSV-1 replication were identified by screening a druggable genome small interfering RNA (siRNA) library (4 siRNAs per gene) targeting 7,237 human genes against a HSV-1 reporter virus expressing the enhanced green fluorescent protein in the epithelial HEK cells overexpressing Med23 transiently (Hela) cell line, due to their ease of transfection and susceptibility to HSV-1 infection [34]
Summary
Up to 90% of the global population is infected with the aherpesvirus Herpes simplex virus type I (HSV-1). Whilst HSV-1 is largely responsible for outbreaks of vesicular oral skin lesions (fever blisters, or cold sores), it can cause a variety of more severe diseases including encephalitis, meningitis and keratitis [1,2]. HSV-1 establishes lytic (epithelial cells) and asymptomatic latent infection (sensory neurons in trigeminal and sacral ganglia) which undergoes periodic reactivation [3]. The equilibrium between these two infection states requires a fine balance between innate and adaptive immune responses, and viral immune evasion mechanisms [4].
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