A systematic analysis of host factors reveals a med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication
| Autor: | Gao, Shou-Jiang, Griffiths, Samantha J., Koegl, Manfred, Boutell, Chris, Zenner, Helen L., Crump, Colin M., Pica, Francesca, Gonzalez, Orland, Friedel, Caroline C., Barry, Gerald, Martin, Kim, Craigon, Marie H., Chen, Rui, Kaza, Lakshmi N., Fossum, Even, Fazakerley, John K., Efstathiou, Stacey, Volpi, Antonio, Zimmer, Ralf, Ghazal, Peter, Haas, Jürgen |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Interferon Regulatory Factor-7
viruses RNA polymerase II Herpesvirus 1 Human Virus Replication medicine.disease_cause 0302 clinical medicine RNA interference Interferon Molecular Cell Biology Biology (General) Genetics 0303 health sciences Mediator Complex biology Systems Biology HSV Genomics Up-Regulation 3. Good health Infectious Diseases Medicine RNA Polymerase II Research Article medicine.drug Settore MED/17 - Malattie Infettive QH301-705.5 Immunology Polymorphism Single Nucleotide Microbiology Virus 03 medical and health sciences Virology medicine Humans Biology Molecular Biology 030304 developmental biology Neurotropic virus Genome Human Interleukins Herpes Simplex RC581-607 Herpes simplex virus Viral replication biology.protein IRF7 Clinical Immunology Parasitology Interferons Immunologic diseases. Allergy Gene Deletion 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | PLoS Pathogens Griffiths, S J, Koegl, M, Boutell, C, Zenner, H L, Crump, C M, Pica, F, Gonzalez, O, Friedel, C C, Barry, G, Martin, K, Craigon, M H, Chen, R, Kaza, L N, Fossum, E, Fazakerley, J K, Efstathiou, S, Volpi, A, Zimmer, R, Ghazal, P & Haas, J 2013, ' A Systematic Analysis of Host Factors Reveals a Med23-Interferon-λ Regulatory Axis against Herpes Simplex Virus Type 1 Replication ', PLoS Pathogens, vol. 9, no. 8, e1003514 . https://doi.org/10.1371/journal.ppat.1003514 PLoS Pathogens, Vol 9, Iss 8, p e1003514 (2013) |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1003514 |
| Popis: | 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. Author Summary Herpes simplex virus type 1 (HSV-1) infects the vast majority of the global population. Whilst most people experience the relatively mild symptoms of cold sores, some individuals suffer more serious diseases like viral meningitis and encephalitis. HSV-1 is also becoming more common as a cause of genital herpes, traditionally associated with HSV-2 infection. Co-infection with HSV-2 is a major contributor to HIV transmission, so a better understanding of HSV-1/HSV-2 disease has wide implications for global healthcare. After initial infection, all herpesviruses have the ability to remain dormant, and can awaken to cause a symptomatic infection at any stage. Whether the virus remains dormant or active is the result of a finely tuned balance between our immune system and evasion techniques developed by the virus. In this study we have found a new method by which the replication of the virus is counteracted. The cellular protein Med23 was found to actively induce an innate anti-viral immune response in the form of the Type III interferons (IFN-lambda), by binding IRF7, a key regulator of interferons, and modulating its activity. Interferon lambda is well known to be important in the control of Hepatitis C infection, and a genetic mutation correlating to an increase in interferon lambda levels is strongly linked to clearance of infection. Here we find the same association between this genetic mutation and the clinical severity of recurrent cases of HSV-1 infection (coldsores). These data identify a Med23-interferon lambda regulatory axis of innate immunity, show that interferon lambda plays a significant role in HSV-1 infection, and contribute to the expanding evidence for interferon lambda in disease control. |
| Databáze: | OpenAIRE |
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