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Inhibition of CD83 Alleviates Systemic Inflammation in Herpes Simplex Virus Type 1-Induced Behcet's Disease Model Mouse.

ABSTRACT: Behçet's disease (BD) is an autoinflammatory disease that can lead to life- and sight-threating complications. Dendritic cells (DCs) are the most potent antigen-presenting cells that can regulate multiple inflammatory pathways. The objective of this study was to investigate the association of the DC stimulatory molecule CD83 with BD. Frequencies of costimulatory molecules expressing DCs in peripheral blood leukocytes (PBL) were measured by flow cytometry (FACS). The severity of symptoms in HSV-1-induced BD symptomatic mice was also assessed. Frequencies of CD83-positive cells were significantly increased in mice exhibiting BD symptoms, compared to those in asymptomatic mice. Abatacept, a CD80/86 blocker, significantly decreased the frequencies of CD83-positive cells in a time- and dose-dependent manner. BD symptomatic mice treated with Abatacept showed gradual reduction in the severity score of symptoms. Intraperitoneal injection of CD83 siRNA significantly reduced the frequencies of CD83-positive cells in PBL and peritoneal macrophages. After CD83 siRNA injection, BD symptoms of mice were improved and disease severity was decreased. Discontinuation of CD83 siRNA deteriorated symptoms while readministration of CD83 siRNA again improved BD symptoms of mice. These results clearly indicate the involvement of CD83-expressing cells in the inflammatory symptoms of BD. Therefore, CD83 might be useful as a therapeutic target for BD.

SUBMITTER: Islam SMS

PROVIDER: S-EPMC6754941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Combined treatment of Taraxaci Herba and R7050 alleviates the symptoms of herpes simplex virus-induced Behcet's disease in rats.

Project description:BackgroundBehçet's disease (BD) is a chronic inflammatory systemic disease that affects multiple organs. The causes of BD are still unknown, but it is primarily characterized by autoimmune reaction in the blood vessels. Current research focuses on treatments that can reduce the non-typical inflammatory responses of BD. Nevertheless, studies on improving the inflammatory effect of BD using inflammation mechanisms are still insufficient. Therefore, we conducted the integrated treatments related to inflammation modulation and achieved alleviation of symptoms in BD mice.MethodsTo understand the complex etiology of BD and compare its management, the herpes simplex virus (HSV)-induced BD mouse model was used. In order to alleviate the inflammatory response in BD mice, Taraxaci Herba (TH, herbal medicine), R7050-a TNFα inhibitor, and a mixture of TH and R7050 were injected for 2 weeks repetitively. The SCORAD index was examined to evaluate the cutaneous inflammations. In addition, histological changes and inflammatory factors were analyzed.ResultsRepetitive injection of TH and/or R7050 reduced the symptoms of BD and significantly decreased IL-6, IL-1β, and TNFα in blood sera. Moreover, this treatment reduced the ulcers and the deterioration of skin.ConclusionsThe results of our study showed that the down-regulation of inflammatory factors is related to the control of immune responses in BD models, suggesting that a mixed drug treatment may be more effective in improving the condition of BD.

| S-EPMC8059053 | biostudies-literature

Interrelationship of Stress, Environment, and Herpes Simplex Virus Type-1 on Behcet's Disease: Using a Mouse Model.

Project description:The purpose of this study was to investigate effects of stress and environment factors on the induction of Behçet's disease (BD) using HSV-1 infected mouse model. BD is a chronic multisystemic inflammatory disease of unknown etiology. Environmental factors, immune dysfunction, and herpes simplex virus type-1 (HSV) infection might be triggers of BD. To investigate effects of environmental factors on the incidence of BD, HSV was inoculated into mice. Mice were then maintained in conventional facility or SPF facility to compare BD incidence rates. The incidence of BD was also tracked by adding stressors such as substance P (anxiety stress), 4°C (cold stress), xanthine sodium salt (oxidative stress), or 77 dB noise (noise stress). To clarify immune mechanisms involved in the difference in BD incidence caused by various stresses, dendritic cell activation markers were analyzed using flow cytometry. The combination of conventional environment, noise stress, and HSV had the highest rate of BD (38.1%) among all groups. However, HSV inoculated group in a SPF environment had the lowest incidence (2.2%). Frequencies of dendritic cell activation markers such as CD40, CD83, CD80, and CD86 were expressed differently under various stresses. Noise stress increased frequencies of CD83 positive cells. Noise stress also upregulated transcription factors T-bet and ROR-γt. Different gut microbiota compositions were observed between SPF and conventional environment by 16S rRNA sequence analysis. Environment and stress influenced the incidence of HSV-induced BD. Microbial diversity due to environmental differences might be one explanation for regional differences in the incidence of BD.

| S-EPMC8044423 | biostudies-literature

The role of CCR1 and therapeutic effects of anti-CCL3 antibody in herpes simplex virus-induced Behcet's disease mouse model.

Project description:Behçet's disease (BD) is a chronic systemic inflammatory disease with unclear etiopathogenesis. Although gene variants of CC chemokine receptor type 1 (CCR1) have been reported, the protein expression of CCR1 in patients with BD remains unclear. The objective of this study was to analyze the frequencies of CCR1+ cells in a herpes simplex virus-induced mouse model of BD. The frequencies of CCR1+ cells on the surface and in the cytoplasm of peripheral blood mononuclear cells and lymph nodes were analyzed by flow cytometry. The CCR1+ cells were significantly down-regulated in BD mice compared with the normal control and symptom-free control mice. Colchicine and pentoxifylline treatment improved the symptoms of BD and increased the frequencies of CCR1+ cells in BD mice. Treatment with chemokine CC motif ligand 3 (CCL3), a ligand of CCR1, caused BD symptoms to deteriorate in 10 of 16 BD mice (62·5%) via down-regulation of CCR1+ cells. Anti-CCL3 antibody treatment ameliorated BD symptoms in 10 of 20 mice (50%) and significantly decreased the disease severity score compared with CCL3-treated BD mice (P = 0·01) via up-regulation of CCR1+ cell frequencies. In patients with BD, plasma levels of CCL3 in an active state were significantly higher than in healthy control individuals (P = 0·02). These results show that the up-regulation of CCR1+ cells was related to the control of systemic inflammation of BD in mouse models.

| S-EPMC6797864 | biostudies-literature

Herpes Simplex Virus 1

Project description:The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin

| PRJNA338711 | ENA

Herpes Simplex Virus Suppressive Therapy in Herpes Simplex Virus-2/Human Immunodeficiency Virus-1 Coinfected Women Is Associated With Reduced Systemic CXCL10 But Not Genital Cytokines.

Project description:Herpes simplex virus type-2 (HSV-2) may heighten immune activation and increase human immunodeficiency virus 1 (HIV-1) replication, resulting in greater infectivity and faster HIV-1 disease progression. An 18-week randomized, placebo-controlled crossover trial of 500 mg valacyclovir twice daily in 20 antiretroviral-naive women coinfected with HSV-2 and HIV-1 was conducted and HSV-2 suppression was found to significantly reduce both HSV-2 and HIV-1 viral loads both systemically and the endocervical compartment.To determine the effect of HSV-2 suppression on systemic and genital mucosal inflammation, plasma specimens, and endocervical swabs were collected weekly from volunteers in the trial and cryopreserved. Plasma was assessed for concentrations of 31 cytokines and chemokines; endocervical fluid was eluted from swabs and assayed for 14 cytokines and chemokines.Valacyclovir significantly reduced plasma CXCL10 but did not significantly alter other cytokine concentrations in either compartment.These data suggest genital tract inflammation in women persists despite HSV-2 suppression, supporting the lack of effect on transmission seen in large scale efficacy trials. Alternative therapies are needed to reduce persistent mucosal inflammation that may enhance transmission of HSV-2 and HIV-1.

| S-EPMC5117823 | biostudies-literature

Inhibition of herpes simplex virus type 1 by small interfering RNA.

Project description:BackgroundRNA interference, a conserved mechanism in which a sequence-specific gene-silencing process is mediated by small interfering RNA (siRNA), is a promising method of gene therapy in treating a variety of viral diseases.AimTo investigate the antiviral effects of siRNA on herpes simplex virus type 1 (HSV-1) replication in Vero cells.MethodsThe antiviral effects of siRNA duplexes targeting the VP16 and DNA polymerase genes of HSV-1 were evaluated by yield-reduction and plaque-reduction assays. The effect of siRNA on the expression of target genes was measured by real-time quantitative reverse transcription PCR.ResultsTwo siRNA duplexes (siRNA-1, targeting VP16, and siRNA-4, targeting DNA polymerase), were found to be highly effective in inhibiting HSV-1 replication. siRNA-1 and siRNA-4 reduced HSV-1 replication by around 2 log(10) and 1 log(10) in the yield--reduction assay and by approximately 85% and approximately 70% in the plaque-reduction assay, respectively. Significant decreases in the mRNA level of VP16 and DNA polymerase genes were detected after viral infection in the Vero cells pretreated with siRNA-1 and siRNA-4, respectively.Conclusion:These results indicate that siRNA can potently inhibit HSV-1 replication in vitro, suggesting that siRNA-based antiviral therapy may be a potential effective therapeutic alternative for patients with HSV-1 infection.

| S-EPMC7162058 | biostudies-literature

Glutamine supplementation suppresses herpes simplex virus reactivation

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-08-30 | GSE95716 | GEO

Screening Method for CRISPR/Cas9 Inhibition of a Human DNA Virus: Herpes Simplex Virus.

Project description:The efficiency of cleavage of individual CRISPR/Cas9-sgRNAs remains difficult to predict based on the CRISPR target sequence alone. Different intracellular environments (dependent on cell type or cell cycle state for example) may affect sgRNA efficiency by altering accessibility of genomic DNA through DNA modifications such as epigenetic marks and DNA-binding proteins (e.g., histones) as well as alteration of the chromatin state of genomic DNA within the nucleus. We recently reported a multi-step screening method for the identification of efficient sgRNAs targeting the Herpes simplex virus (HSV-1) genome and reported a differential mechanism for viral inhibition by CRISPR-Cas9 in the latent versus lytic phase. The screening platform detailed in this protocol allows step-by-step testing of the efficiency of cleavage in a cell-free system and in the context of viral target cells such as human foreskin fibroblasts followed by functional testing of the effects of CRISPR/sgRNA on viral protein expression, replication, and reactivation. This strategy could be readily applied to other target cells such as pluripotent stem cell-derived human sensory neurons or other human DNA viruses.

| S-EPMC7842287 | biostudies-literature

Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis.

Project description:Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1-3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis.

| S-EPMC5743594 | biostudies-literature

Glutamine supplementation suppresses herpes simplex virus reactivation III

Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.

2017-08-30 | GSE95715 | GEO

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