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Nrf2 Negatively Regulates Type I Interferon Responses and Increases Susceptibility to Herpes Genital Infection in Mice.

ABSTRACT: Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections for which no effective vaccines or prophylactic treatment currently exist. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in the detoxification of reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. Here, we evaluated the importance of Nrf2 in the control of HSV-2 genital infection, and its role in the regulation of HSV-induced innate antiviral immunity. Comparison of antiviral gene expression profile by RNA-sequencing analysis of wild type and Nrf2-mutant (Nrf2 AY/AY ) murine macrophages showed an upregulation at the basal level of the type I interferon-associated gene network. The same basal increased antiviral profile was also observed in the spleen of Nrf2 -/- mice. Interestingly, the lack of Nrf2 in murine cells was sufficient to increase the responsiveness to HSV-derived dsDNA and protect cells from HSV-2 infection in vitro. Surprisingly, there was no indication of an alteration in STING expression in murine cells as previously reported in cells of human origin. Additionally, genetic activation of Nrf2 in Keap1 -/- mouse embryonic fibroblasts increased HSV-2 infectivity and replication. Finally, using an in vivo vaginal herpes infection model, we showed that Nrf2 controlled early innate immune responses to HSV-2 without affecting STING expression levels. Nrf2 -/- mice exhibited reduced viral replication that was associated with higher level of type I interferons in vaginal washes. Nrf2 -/- mice also displayed reduced weight loss, lower disease scores, and higher survival rates than wild type animals. Collectively, these data identify Nrf2 as a negative regulator of the interferon-driven antiviral response to HSV-2 without impairing STING mRNA and protein expression levels in murine cells.

SUBMITTER: Gunderstofte C

PROVIDER: S-EPMC6742979 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Nrf2 Negatively Regulates Type I Interferon Responses and Increases Susceptibility to Herpes Genital Infection in Mice.

Gunderstofte Camilla C Iversen Marie Beck MB Peri Suraj S Thielke Anne A Balachandran Siddharth S Holm Christian Kanstrup CK Olagnier David D

Frontiers in immunology 20190906

Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections for which no effective vaccines or prophylactic treatment currently exist. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in the detoxification of reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. Here, we evaluated the importance of Nrf2 in the control of HSV-2 genital infection, and its role in the regulation ...[more]

PMID: 31555293

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Project description:IFNL4-?G/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-?4 protein is generated only in individuals who carry the IFNL4-?G allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-?G, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-?G/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women's Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)-infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV-1 and HSV-2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV-2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-?G/TT genotyping was determined by TaqMan. We compared women with IFNL4-?G/?G or IFNL4-TT/?G genotypes (i.e., IFNL4-?G carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV-1 and 79.0% were positive for HSV-2. We observed no association between IFNL4-?G/TT genotype and any outcome: HSV-1 or HSV-2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV-2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV-2 DNA level (p = 0.68). In this large prospective study, IFNL4-?G/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.

Dataset Information

Nrf2 Negatively Regulates Type I Interferon Responses and Increases Susceptibility to Herpes Genital Infection in Mice.

Publications

Nrf2 Negatively Regulates Type I Interferon Responses and Increases Susceptibility to Herpes Genital Infection in Mice.

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