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-sca...
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2013
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oai:doaj.org-article:c1319d0c08484c8a870675e8787025592021-11-18T06:07:48ZA systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.1553-73661553-737410.1371/journal.ppat.1003514https://doaj.org/article/c1319d0c08484c8a870675e8787025592013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23950709/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Herpes 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.Samantha J GriffithsManfred KoeglChris BoutellHelen L ZennerColin M CrumpFrancesca PicaOrland GonzalezCaroline C FriedelGerald BarryKim MartinMarie H CraigonRui ChenLakshmi N KazaEven FossumJohn K FazakerleyStacey EfstathiouAntonio VolpiRalf ZimmerPeter GhazalJürgen HaasPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 8, p e1003514 (2013) |
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| collection |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Samantha J Griffiths Manfred Koegl Chris Boutell Helen L Zenner Colin M Crump Francesca Pica Orland Gonzalez Caroline C Friedel Gerald Barry Kim Martin Marie H Craigon Rui Chen Lakshmi N Kaza Even Fossum John K Fazakerley Stacey Efstathiou Antonio Volpi Ralf Zimmer Peter Ghazal Jürgen Haas A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| description |
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. |
| format |
article |
| author |
Samantha J Griffiths Manfred Koegl Chris Boutell Helen L Zenner Colin M Crump Francesca Pica Orland Gonzalez Caroline C Friedel Gerald Barry Kim Martin Marie H Craigon Rui Chen Lakshmi N Kaza Even Fossum John K Fazakerley Stacey Efstathiou Antonio Volpi Ralf Zimmer Peter Ghazal Jürgen Haas |
| author_facet |
Samantha J Griffiths Manfred Koegl Chris Boutell Helen L Zenner Colin M Crump Francesca Pica Orland Gonzalez Caroline C Friedel Gerald Barry Kim Martin Marie H Craigon Rui Chen Lakshmi N Kaza Even Fossum John K Fazakerley Stacey Efstathiou Antonio Volpi Ralf Zimmer Peter Ghazal Jürgen Haas |
| author_sort |
Samantha J Griffiths |
| title |
A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| title_short |
A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| title_full |
A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| title_fullStr |
A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| title_full_unstemmed |
A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| title_sort |
systematic analysis of host factors reveals a med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/c1319d0c08484c8a870675e878702559 |
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