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Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis.

ABSTRACT: STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3' untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING's antiviral action.

SUBMITTER: Sharma N

PROVIDER: S-EPMC8483329 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledIn order to understand factors that may influence latency-associated transcription and latency-associated transcript (LAT) phenotypes, we studied the expression of the herpes simplex virus 2 (HSV-2) LAT-associated microRNAs (miRNAs). We mapped the transcription initiation sites of all three primary miRNA transcripts and identified the ICP4-binding sequences at the transcription initiation sites of both HSV-2 LAT (pri-miRNA for miR-I and miR-II, which target ICP34.5, and miR-III, which targets ICP0) and L/ST (a pri-miRNA for miR-I and miR-II) but not at that of the primary miR-H6 (for which the target is unknown). We confirmed activity of the putative HSV-2 L/ST promoter and found that ICP4 trans-activates the L/ST promoter when the ICP4-binding site at its transcription initiation site is mutated, suggesting that ICP4 may play a dual role in regulating transcription of L/ST and, consequently, of miR-I and miR-II. LAT exon 1 (containing LAT enhancer sequences), together with the LAT promoter region, comprises a bidirectional promoter required for the expression of both LAT-encoded miRNAs and miR-H6 in latently infected mouse ganglia. The ability of ICP4 to suppress ICP34.5-targeting miRNAs and to activate lytic viral genes suggests that ICP4 could play a key role in the switch between latency and reactivation.ImportanceThe HSV-2 LAT and viral miRNAs expressed in the LAT region are the most abundant viral transcripts during HSV latency. The balance between the expression of LAT and LAT-associated miRNAs and the expression of lytic viral transcripts from the opposite strand appears to influence whether individual HSV-infected neurons will be latently or productively infected. The outcome of neuronal infection may thus depend on regulation of gene expression of the corresponding primary miRNAs. In the present study, we characterize promoter sequences responsible for miRNA expression, including identification of the primary miRNA 5' ends and evaluation of ICP4 response. These findings provide further insight into the virus' strategy to tightly control expression of lytic cycle genes (especially the neurovirulence factor, ICP34.5) and suggest a mechanism (via ICP4) for the transition from latency to reactivated productive infection.

Project description:BACKGROUND:Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis. OBJECTIVES:To compare the relative effectiveness of antiviral agents, interferon, and corneal débridement in the treatment of acute HSV epithelial keratitis. SEARCH STRATEGY:We searched CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (January 1950 to October 2010), EMBASE (January 1980 to October 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2010), Zetoc (British Library's Electronic Table of Contents), System for Information on Grey Literature in Europe (openSIGLE), Biosciences Information Service (BIOSIS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), Japan Information Center of Science and Technology (JICST-EPlus), and China Academic Journals database (CAJ) via China National Knowledge Infrastructure (CNKI) with citations confirmed using China/Asia On Demand (COAD). There were no language or date restrictions in the search for trials. All databases except CNKI and COAD were last searched on 27 October 2010, CNKI and COAD were searched on 1 April 2010. We also searched literature digests, conference proceedings and reference lists. SELECTION CRITERIA:Of 152 eligible studies,106 comparative treatment trials involving 5872 eyes with dendritic or geographic epithelial keratitis were analysed for corneal healing over two weeks. DATA COLLECTION AND ANALYSIS:Interventions were compared at 14 days after trial enrolment by calculating a risk ratio (RR) that was adjusted with indirect RR, assessed by an inconsistency index (I(2) ) and supplemented by a seven-day RR and a hazard ratio (HR). MAIN RESULTS:Idoxuridine, though uncertainly better in healing outcome than control because of few trials with 14-day follow up, allowed earlier corneal re-epithelialisation. Vidarabine resulted in a significantly better outcome than placebo in one trial (RR 1.96; 95% CI 1.10 to 3.49). Compared to idoxuridine, in combined direct and indirect analyses, vidarabine (RR 1.11; 95% CI 1.03 to 1.19), trifluridine (RR 1.31; 95% CI 1.20 to 1.42), acyclovir (RR 1.23; 95% CI 1.16 to 1.31), brivudine (RR 1.38; 95% CI 1.18 to 1.61), and ganciclovir (RR 1.40; 95% CI 1.25 to 1.57) were significantly more effective. Trifluridine (RR 1.12; 95% CI 1.04 to 1.21) and acyclovir (RR 1.11; 95% CI 1.05 to 1.19) appeared more effective than vidarabine. No significant differences were found in comparisons between acyclovir, trifluridine and brivudine. The comparison of ganciclovir to acyclovir was limited by heterogeneity and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as topical antiviral therapy. Compared to antiviral monotherapy, the combination of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with débridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes but may have accelerated healing. The corneal epithelial healing outcome was improved when antiviral therapy was added to débridement (RR 1.21; 95% CI 1.04 to 1.42). AUTHORS' CONCLUSIONS:Trifluridine and acyclovir are more effective than idoxuridine or vidarabine, and similar in therapeutic effectiveness. Brivudine and ganciclovir are at least as effective as acyclovir. While not improving outcome, the combination of interferon and an antiviral agent may speed healing. The effectiveness of corneal epithelial débridement is improved by an antiviral agent.

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Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis.

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