Dataset Information

HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

ABSTRACT: It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infection enhances TLR9 expression at both mRNA and protein levels. Such enhancement is virus replication-dependent and CpG-independent, while the HSV-2-mediated upregulation of TLR9 does not activate TLR9 signaling pathway. Mechanistically, a SP1 binding site on TLR9 promoter appears to be essential for HSV-2-induced TLR9 transactivation. Upon HSV-2 infection, SP1 translocates from the cytoplasm to the nucleus, and consequently binds to TLR9 promoter. By using specific inhibitors, the JNK signaling pathway is shown to be involved in the HSV-2-induced TLR9 transactivation, while HSV-2 infection increases the phosphorylation but not the total level of JNK. In agreement, antagonism of JNK signaling pathway inhibits the HSV-2-induced SP1 nuclear translocation. Taken together, our study demonstrates that HSV-2 infection of human genital epithelial cells promotes TLR9 expression through SP1/JNK signaling pathway. Findings in this study provide insights into HSV-2-host interactions and potential targets for immune intervention.

SUBMITTER: Hu K

PROVIDER: S-EPMC7065266 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

Hu Kai K Fu Ming M Wang Jun J Luo Sukun S Barreto Mariana M Singh Rubin R Chowdhury Tasnim T Li Mei M Zhang Mudan M Guan Xinmeng X Xiao Juhua J Hu Qinxue Q

Frontiers in immunology 20200304

It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infectio ...[more]

PMID: 32194565

Similar Datasets

Project description:Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNβ, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNβ were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNβ had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNβ led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

Project description:ImportanceHerpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.ObjectiveTo inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Design, setting, and participantsProspective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.ExposuresFirst-episode genital HSV-1 infection.Main outcomes and measuresGenital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.ResultsAmong the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.Conclusions and relevanceGenital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.

Dataset Information

HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

Publications

HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets