A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.
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.
Division of Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Samantha J
SJ
Griffiths
Manfred
M
Koegl
Chris
C
Boutell
Helen L
HL
Zenner
Colin M
CM
Crump
Francesca
F
Pica
Orland
O
Gonzalez
Caroline C
CC
Friedel
Gerald
G
Barry
Kim
K
Martin
Marie H
MH
Craigon
Rui
R
Chen
Lakshmi N
LN
Kaza
Even
E
Fossum
John K
JK
Fazakerley
Stacey
S
Efstathiou
Antonio
A
Volpi
Ralf
R
Zimmer
Peter
P
Ghazal
Jürgen
J
Haas
D017353:Gene Deletion; D015894:Genome, Human; D006367:HeLa Cells; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D056892:Mediator Complex / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012319:RNA Polymerase II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication / Q000502:physiology*; D000095022:Interferon Lambda
D050839:Interferon Regulatory Factor-7; D007372:Interferons; D007378:Interleukins; D056892:Mediator Complex; D012319:RNA Polymerase II; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494234:IRF7 protein, human; C492159:MED23 protein, human