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Study on Role of Toll-like Receptor 7 in Hepatitis B Virus Infection Pathogenesis

Author: WuHong
Tutor: WuXiaoMan
School: Guangzhou Medical College
Course: Immunology
Keywords: TLRs HBV Loxoribine HepG2.2.15 cells PBMC
CLC: R512.62
Type: Master's thesis
Year: 2010
Downloads: 88
Quote: 0
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Abstract


Background Hepatitis B virus (Hepatitis B virus, HBV) infection is a global health problem. Some people first infected with HBV can not completely get rid of the virus become chronic HBV carriers or patients with chronic hepatitis B, and even the development of cirrhosis, liver cancer and serious harm to human health. Persistent HBV infection and host-specific immune tolerance, interferon α level is low, the lack of T cell responses or plasmacytoid dendritic cells decreased and dysfunction related, but the exact mechanism remains to be further studied. Toll-like receptor (TLR) is found in recent years, a class of pattern recognition receptors in innate and acquired immune recognition of pathogen-associated molecular pattern (PAMP) plays the role of an important bridge [1]. TLR7 is one of the important members of the TLR family, their ligand binding can induce interferon, interleukin and tumor necrosis factor cytokine production, play antiviral activity [2,3]. TLR7 agonist imiquimod Mott (IMQ/R-847)) and of Ai Shatuo Li Bin (Loxribine, congeners), were used for skin cancer and chronic hepatitis C treatment [4,5]. TLR7 another ligand Resiquimod (R-848) through the induction of IFN-α, IFN-β generated significantly inhibit HBV replication [2]. The TLR7 essential role of antiviral immune significantly reduced TLR7 expression in peripheral blood mononuclear cells of patients with chronic hepatitis B [6]. However, at home and abroad for HBV infection TLR7 expression regulatory impact study little effect and mechanism of TLR7 in the incidence of hepatitis B is uncertain. The research by the TLR7-mediated in vitro anti-HBV effects and transfected with HBV TLR7 expression regulation impact study of TLR7 role in the pathogenesis of hepatitis B. By detecting TLR7-mediated chronic hepatitis B patients with peripheral blood mononuclear cells to produce IFN-α, IL-12 content changes, investigate the function of chronic HBV infection on immune cells TLR7 injury and significance of the role of TLR7 in chronic HBV infection and possible mechanism, the reference period of TLRs mediated innate immune looking for new targets and the development of new drugs to treat hepatitis B preliminary experimental basis. Research purposes. TLR7-specific ligand Loxoribine stimulus HepG2.2.15 cell strains to explore TLR7-mediated in vitro anti-HBV effects and mechanism. By detecting TLR7-specific ligand Loxoribine TLR7 expression, stimulate HBV before and after transfection of HepG2 and HepG2.2.15 cell lines to investigate the expression and regulation of TLR7 transfected with HBV, elaborated TLR7 in the pathogenesis of hepatitis B role. By detecting TLR7-mediated chronic hepatitis B patients with peripheral blood mononuclear cells to produce IFN-α, IL-12 content changes, investigate the function of chronic HBV infection on immune cells TLR7 injury and significance of TLR7 role in chronic HBV infection in and mechanisms. Research methods chosen stable markers of HBV particles and HBV antigen secretion HepG2.2.15 cell lines transfected with HBV cell model, using ELISA and real-time PCR assay TLR7 specificity the ligand Loxoribine of HepG2.2.15 cells HBsAg of HBeAg secretion and HBV DNA replication inhibition explore TLR7-mediated in vitro anti-HBV effects. 2 MTT colorimetric assay TLR7 the specific ligand Loxoribine stimulus HepG2.2.15 cell toxicity. Flow cytometry cytometry HepG2 of HepG2.2.15 cell lines intracellular TLR7 protein expression levels, and specific ligand Loxoribine induced its expression regulation. 4 ELISA assay TLR7-specific ligand Loxoribine stimulate chronic HBV infected patients and healthy human peripheral blood mononuclear cells to produce IFN-α, IL-12 content changed, the evaluation of chronic HBV infection TLR7 function of immune cells. Results in TLR7 the specific ligand Loxoribine role, can effectively inhibit the secretion HepG2.2.15 cells HBsAg and HBV DNA replication, a dose-and time-dependent inhibition of secretion of HBsAg. No inhibitory effect on the secretion of HBeAg. 2. Low concentrations Loxoribine to the HepG2.2.15 cell growth of certain inhibitory, but with the increased concentration of the ligand, no significant toxic effects on cell growth. 3. HepG2 and HepG2.2.15 intracellular both TLR7 expression, but transfection the HBV genome HepG2.2.15 intracellular TLR7 expression was significantly lower than non-transfected HepG2 cells. TLR7-specific ligand Loxoribine induced HepG2 and HepG2.2.15 cells intracellular of TLR7 expression of volume increase, but the difference was not statistically significant. 4. Hepatitis B virus carrier group and the group of patients with chronic hepatitis B in peripheral blood mononuclear cell culture supernatants of IFN-α level was significantly lower than the healthy control group; chronic hepatitis B patients IL-12 levels were significantly higher than the healthy control group; hepatitis B virus carrier between the group and the group of patients with chronic hepatitis B, PBMC culture supernatant of IFN-α and IL-12 levels was no significant difference. 5. TLR7 the specific ligand Loxoribine stimulate cultured, healthy control group peripheral blood mononuclear cell culture supernatants of IFN-alpha and IL-12 levels were significantly elevated hepatitis B virus carrier group and chronic hepatitis B patients with IFN-α, IL-12 levels were higher, but the difference was not statistically significant. Conclusion 1. Specific ligands Loxoribine has significant anti-HBV suppression of HBV may TLR7-mediated role in viral replication and protein synthesis and other aspects. 2. HBV infection inhibited TLR7 expression and specific ligand Loxoribine induction may play a significant role in anti-HBV that TLR7 downregulation may be involved in the pathogenesis of hepatitis B. Chronic HBV infection in patients with peripheral blood mononuclear cells TLR7 impaired, INF-α produce low levels of IL-12 regulation function disorders, which may lead to persistent HBV infection.

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CLC: > Medicine, health > Internal Medicine > Infectious disease > Viral infections > Viral Hepatitis > Hepatitis B
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