HCV, Alcohol and Host Defense
HCV、酒精和宿主防御
基本信息
- 批准号:8734297
- 负责人:
- 金额:$ 35.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-15 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alcohol consumptionAlcoholsAntigen PresentationAntiviral AgentsBlood CirculationCD81 geneCell CommunicationCell physiologyCellsChronicChronic Hepatitis CDefectDendritic CellsDinoprostoneDouble-Stranded RNAFrequenciesFutureGoalsHCV Liver DiseaseHepatitis CHepatitis C virusHepatocyteHost DefenseHumanIL2RA geneImmuneImmune systemImmunityIn VitroIndividualInflammationInflammatoryInstructionInterferon-alphaInterferonsInterleukin-10Interleukin-12Kupffer CellsLiverLiver diseasesMeasuresMediatingMethodsMicroRNAsMolecularMyelogenousNatural ImmunityOutcomePathway interactionsPatientsPhenotypePlayPopulationProductionProteinsRNARNA VirusesRegulationRegulatory T-LymphocyteRoleSignal TransductionSmall Interfering RNASpecimenT cell responseT-Cell ActivationT-LymphocyteTLR2 geneTLR3 geneTestingTherapeutic InterventionTransforming Growth Factor betaViralViral ProteinsVirionVirus Activationadaptive immunityalcohol abuse therapyalcohol effectalcohol exposurebasechronic liver diseasedesensitizationgene inductionhepatoma cellhuman TLR7 proteininnate immune functioninterleukin-23liver biopsyliver inflammationmacrophagemonocytenoveloverexpressionreceptorresearch studyresponsevirus core
项目摘要
Innate immune recognition of the single stranded RNA (ssRNA) virus and induction of a strong antiviral
immunity play a critical role in the outcome of hepatitis C virus (HCV) infection. Alcohol consumption
contributes to inflammation, innate immune defects, and HCV-induced progression of liver disease. HCV
interacts with immune cells in the liver through interactions between HCV-infected hepatocytes or in the
circulation in the form of infectious virus particle or its abundantly produced viral proteins. HCV represents
danger signals for the host through Toll like receptor 7 and 8 that recognize ssRNA, TLR3 that senses
dsRNA or TLR2 that is activated by HCV core and NSS proteins. These TLRs are expressed in immune cells
and in hepatocytes but little is known about the role of interactions between HCV infected hepatocytes and
innate immune cells such as monocytes and dendritic cells (DC) in the pathomechanism of HCV infection.
Our studies demonstrated that chronic HCV infection as well as alcohol treatment results in increased
monocyte pro-inflammatory activation but impaired IFN production by plasmacytoid dendritic cells.
Therefore, we hypothesize that HCV and alcohol, individually and together, interfere with antiviral host
defense at the level of viral recognition receptors and by subverting pivotal functions of monocytes and
dendritic cells. We propose that interaction of innate immune cells (monocytes, macrophages, dendritic cells)
with HCV-infected hepatocytes modulates their function and/or phenotype to result in impaired innate and
adaptive immunity. We hypothesize that HCV-mediated signals play a role in HCV-induced alterations in
dendritic cells (mDCI, mDC2, pDC) and contribute to the reduced T cell responses in HCV infection by
induction of CD4+CD25+ regulatory T cells. The Specific Aims of this proposal are: 1. To determine the
effect of alcohol exposure and HCV on the function and phenotype of monocytes and macrophages, 2. To
investigate mechanisms by which alcohol modulates myeloid Type I dendritic cell-mediated defects of T cell
activation in chronic HCV infection, 3. To evaluate the effects of alcohol on IFN-lambda in HCV infection, 4.
To assess the effect of TLR-mediated/HCV-induced signals in altering dendritic cell functions.
对单链RNA(SSRNA)病毒的先天免疫识别和强抗病毒的诱导
免疫力在丙型肝炎病毒(HCV)感染的结果中起关键作用。饮酒
有助于炎症,先天免疫缺陷和HCV诱导的肝病进展。 HCV
通过HCV感染的肝细胞或中的相互作用与肝脏中的免疫细胞相互作用
以传染病颗粒或其大量产生的病毒蛋白的形式循环。 HCV代表
通过收费(如受体7和8)识别ssRNA,TLR3的危险信号
由HCV核心和NSS蛋白激活的DSRNA或TLR2。这些TLR在免疫细胞中表达
在肝细胞中,关于HCV感染的肝细胞与
HCV感染的病理机理中的固有免疫细胞,例如单核细胞和树突状细胞(DC)。
我们的研究表明,慢性HCV感染以及酒精治疗导致增加
单核细胞促炎性激活,但受质细胞类树突状细胞产生的IFN损害。
因此,我们假设HCV和酒精单独和一起干扰抗病毒宿主
在病毒识别受体水平上的防御和通过颠覆单核细胞的关键功能和
树突状细胞。我们提出了先天免疫细胞(单核细胞,巨噬细胞,树突状细胞)的相互作用
使用HCV感染的肝细胞调节其功能和/或表型,从而导致先天性受损
自适应免疫。我们假设HCV介导的信号在HCV诱导的改变中起作用
树突状细胞(MDCI,MDC2,PDC),并通过降低HCV感染的T细胞反应。
诱导CD4+ CD25+调节T细胞。该提案的具体目的是:1。确定
酒精暴露和HCV对单核细胞和巨噬细胞功能和表型的影响,2。
研究酒精调节髓样型I型树突状细胞介导的T细胞的缺陷的机制
慢性HCV感染中的激活,3。评估酒精对HCV感染中IFN-LAMBDA的影响,4。
评估TLR介导的/HCV诱导的信号在改变树突状细胞功能中的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gyongyi Szabo的其他文献
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{{ truncateString('Gyongyi Szabo', 18)}}的其他基金
Biomarkers of Disease in Alcoholic Hepatitis Administrative Supplement
酒精性肝炎行政补充剂中疾病的生物标志物
- 批准号:
10840220 - 财政年份:2023
- 资助金额:
$ 35.61万 - 项目类别:
Extracellular Vesicles in Alcoholic Liver Disease: Basic and Pre-Clinical Discovery
酒精性肝病中的细胞外囊泡:基础和临床前发现
- 批准号:
10440307 - 财政年份:2020
- 资助金额:
$ 35.61万 - 项目类别:
Extracellular Vesicles in Alcoholic Liver Disease: Basic and Pre-Clinical Discovery
酒精性肝病中的细胞外囊泡:基础和临床前发现
- 批准号:
10167062 - 财政年份:2020
- 资助金额:
$ 35.61万 - 项目类别:
Extracellular Vesicles in Alcoholic Liver Disease: Basic and Pre-Clinical Discovery
酒精性肝病中的细胞外囊泡:基础和临床前发现
- 批准号:
10208640 - 财政年份:2020
- 资助金额:
$ 35.61万 - 项目类别:
Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 4/9
酒精性肝炎临床和转化网络后期临床试验和观察研究 4/9
- 批准号:
10441258 - 财政年份:2019
- 资助金额:
$ 35.61万 - 项目类别:
Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 4/9
酒精性肝炎临床和转化网络后期临床试验和观察研究 4/9
- 批准号:
10022622 - 财政年份:2019
- 资助金额:
$ 35.61万 - 项目类别:
Extracellular Vesicles in Alcoholic Liver Disease: Basic and Pre-Clinical Discovery
酒精性肝病中的细胞外囊泡:基础和临床前发现
- 批准号:
10022712 - 财政年份:2019
- 资助金额:
$ 35.61万 - 项目类别:
Innate immune signaling in alcoholic liver disease
酒精性肝病中的先天免疫信号
- 批准号:
10092047 - 财政年份:2019
- 资助金额:
$ 35.61万 - 项目类别:
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