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Hepatitis B virus particles activate B cells through the TLR2-MyD88-mTOR axis.

ABSTRACT: Host immune control plays a pivotal role in resolving primary hepatitis-B-virus (HBV) infections. The complex interaction between HBV and host immune cells, however, remains unclear. In this study, the transcriptional profiling of specimens from animals infected with woodchuck hepatitis virus (WHV) indicated TLR2 mRNA accumulation as most strongly impacted during WHV infection resolution as compared to other mRNAs. Analysis of blood transcriptional modules demonstrated that monocytes and B-cells were the predominantly activated cell types in animals that showed resolution of infection, which was similar to the response of TLR2-stimulated PBMCs. Further investigation of TLR2-stimulated B-cells pointed at interactions between activated TLR signaling, Akt-mTOR, and glucose metabolic pathways. Moreover, analysis of B-cells from Tlr2^-/-, Trif^-/-, Myd88^-/-, and Trif/Myd88^-/- mice challenged with HBV particles indicated B-cell function and glucose metabolism alterations is TLR2-MyD88-mTOR axis dependent. Overall, our study implicates B-cell TLR2 activation in HBV infection resolution.

SUBMITTER: Li Q

PROVIDER: S-EPMC7791069 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Hepatitis B virus particles activate B cells through the TLR2-MyD88-mTOR axis.

Li Qian Q Wang Jun J Islam Heba H Kirschning Carsten C Lu Hongzhou H Hoffmann Daniel D Dittmer Ulf U Lu Mengji M

Cell death & disease 20210104 1

Host immune control plays a pivotal role in resolving primary hepatitis-B-virus (HBV) infections. The complex interaction between HBV and host immune cells, however, remains unclear. In this study, the transcriptional profiling of specimens from animals infected with woodchuck hepatitis virus (WHV) indicated TLR2 mRNA accumulation as most strongly impacted during WHV infection resolution as compared to other mRNAs. Analysis of blood transcriptional modules demonstrated that monocytes and B-cells ...[more]

PMID: 33414473

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Project description:Background and aimsRecent studies reveal the accumulation of myeloid derived suppressor cells (MDSCs) in human peripheral blood mononuclear cells (PBMCs) following HCV infection, which may facilitate and maintain HCV persistent infection. The mechanisms by which HCV induces MDSCs are poorly understood. In the present study, we investigated the mechanisms by which HCV induces MDSCs that lead to suppression of T cell proliferation and expansion of CD4+Foxp3+ regulatory T cells.MethodsPurified monocytes from healthy donors were cultured with HCV core protein (HCVc) or cell culture-derived HCV virions (HCVcc), and characterized the phenotype and function of these monocytes by flow cytometry, quantitative PCR, ELISA and western blot assays. In addition, peripheral blood from healthy donors and chronic HCV infected patients was collected, and MDSCs and CD4+CD25+CD127- regulatory T cells were analyzed by flow cytometry.ResultsBoth HCVc and HCVcc induced expression of IDO1, PD-L1 and IL-10, and significantly down-regulated HLA-DR expression in human monocytes. HCVc-treated monocytes triggered CD4+Foxp3+ Tregs expansion, and inhibited autologous CD4+ T cell activation in an IDO1-dependent fashion. Our results showed that HCV virions or HCV core proteins induced MDSC-like suppressive monocytes via the TLR2/PI3K/AKT/STAT3 signaling pathway. Monocytes derived from patients with chronic HCV infection displayed MDSCs characteristics. Moreover, the percentages of CD14+ MDSCs and CD4+CD25+CD127- Tregs in chronic HCV infected patients were significantly higher than healthy individuals, and the frequency of MDSCs correlated with CD4+CD25+CD127- Tregs.ConclusionsHCV induced MDSC-like suppressive monocytes through TLR2/PI3K/AKT/STAT3 signaling pathway to induce CD4+Foxp3+ regulatory T cells and inhibit autologous CD4+ T cell activation. It will be of interest to test whether antagonizing suppressive functions of MDSCs could enhance immune responses and virus control in chronic HCV infection.

Project description:BackgroundRecent evidence suggests the neurotrophic potential of hepatitis C virus (HCV). HCV NS3 protein is one of the potent antigens of this virus mediating inflammatory response in different cell types. Microglia being the immune surveillance cells in the central nervous system (CNS), the inflammatory potential of NS3 on microglia was studied. Role of toll like receptor (TLR) ligands Pam2CSK3 and Pam3CSK4 in controlling the NS3 mediated microglial inflammation was studied using microglial cell line CHME3.MethodsIL (Interleukin)-8, IL-6, TNF-? (Tumor nicrosis factor alpha) and IL-1? gene expressions were measured by semi quantitative RT-PCR (reverse transcription-PCR). ELISA was performed to detect IL-8, IL-6, TNF-?, IL-1? and IL-10 secretion. FACS (Flourescent activated cell sorting) was performed to quantify TLR1, TLR2, TLR6, MyD88 (Myeloid differntiation factor 88), IkB-? (I kappaB alpha) and pNF-?B (phosphorylated nuclear factor kappaB) expression. Immunofluorescence staining was performed for MyD88, TLR6 and NF-?B (Nuclear factor kappaB). Student's t-test or One way analysis of variance with Bonferoni post hoc test was performed and p < 0.05 was considered significant.ResultsMicroglia responded to NS3 by secreting IL-8, IL-6, TNF-? and IL-1? via TLR2 or TLR6 mediated MyD88/NF-?B pathway. Transcription factor NF-?B was involved in activating the cytokine gene expression and the resultant inflammatory response was controlled by NF-?B inhibitor, Ro106-9920, which is known to down regulate pro-inflammatory cytokine secretion. Activation of the microglia by TLR agonists Pam3CSK4 and Pam2CSK4 induced immune tolerance against NS3. TLR ligand treatment significantly down regulated pro-inflammatory cytokine secretion in the microglia. IL-10 secretion was suggested as the possible mechanism by which TLR agonists induced immune tolerance. NS3 as such was not capable of self-inducing immune tolerance in microglia.ConclusionIn conclusion, NS3 protein was capable of activating microglia and the inflammatory response could be controlled via blocking the transcription factor NF-?B, or by treating the microglia with TLR ligands which likely function via secreting anti-inflammatory cytokines such as IL-10. This can have therapeutic potential in controlling HCV mediated neuroinflammation.

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Hepatitis B virus particles activate B cells through the TLR2-MyD88-mTOR axis.

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Hepatitis B virus particles activate B cells through the TLR2-MyD88-mTOR axis.

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