Theiler's virus-induced aoptosis: A mechanism for CNS virus persistence
泰勒病毒诱导的细胞凋亡:中枢神经系统病毒持续存在的机制
基本信息
- 批准号:8415819
- 负责人:
- 金额:$ 32.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-02-01 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressApicalApoptosisApoptoticAttenuatedAutoimmune DiseasesAutoimmune ProcessAutoimmunityCD4 Positive T LymphocytesCapsid ProteinsCardiovirusCell DeathCell LineCell surfaceCellsCentral Nervous System InfectionsCessation of lifeD CellsDemyelinating DiseasesDemyelinationsElementsExperimental Animal ModelFamily PicornaviridaeFosteringImmuneImmune responseImmunityIn VitroInfectionInhibition of ApoptosisIntegration Host FactorsLyticMammalian CellMediatingMitochondriaModelingMouse StrainsMultiple SclerosisMusNecrosisNeuraxisNeuronsNonstructural ProteinNoxaeOligodendrogliaOrganismPathway interactionsPhagocytosisPopulationProcessProductionProteinsRNA Virus InfectionsRNA VirusesRepliconResistanceRodentSignal TransductionSystemT cell responseTMEVTransgenic MiceViralViral ProteinsVirulentVirusVirus DiseasesVirus ReplicationWorkarmbeanextracellulargenetic variantin vitro Modelin vivoinhibitor/antagonistkillingsmacrophagememberneurovirulenceneutralizing antibodypublic health relevanceresearch study
项目摘要
DESCRIPTION (provided by applicant): Theiler's murine encephalomyelitis virus (TMEV) is a highly cytolytic RNA virus that produces persistent central nervous system (CNS) infection and immune-mediated demyelination in susceptible strains of mice. TMEV infection provides a relevant experimental animal model for multiple sclerosis. In contrast to persistence of non-cytolytic RNA viruses in which the host cell survives, persistence of lytic RNA viruses in which an infected cell dies requires continuous cell- to-cell spread in order to maintain the infection. In this circumstance, the target cell in which the virus persists ideally should be renewable. The infection should not be highly productive; however, virus-specific host immune responses may control a more productive infection anyway. Macrophages are the principal virus reservoir and provide an in vitro model for TMEV persistence in the mouse CNS. TMEV infected macrophages undergo apoptosis and restrict virus production (<10 pfu/cell), in contrast to infection in other rodent cells, including neurons and oligodendrocytes, where necrotic cell death is associated with high virus yields (200-500 pfu/cell). TMEV infection is required to induce apoptosis in murine macrophages since UV- inactivated virus adsorbed to the cell surface to initiate infection does not induce apoptosis. We have shown that TMEV infection induces apoptosis through the intrinsic pathway that is Bax- mediated and severely restricts infectious virus production in murine macrophages. Our working hypothesis is that TMEV-induced apoptosis is a host cell-specific mechanism providing a means of spreading virus to uninfected macrophages that phagocytose apoptotic remnants containing infectious virus. To understand how TMEV infection triggers apoptosis in murine macrophages and restricts infectious virus production, four specific aims are proposed: 1) finish the identification of upstream signals (apical to the mitochondrion) involved in the intrinsic apoptotic pathway during TMEV virus infection in M1-D macrophages and determine potential differences in apoptosis in primary macrophages from resistant and susceptible strains of mice; 2) inhibit apoptosis in infected mice to assess the effect on TMEV CNS persistence, virus-specific CD4+ T cell responses and demyelinating disease, and examine the effect in transgenic mice deficient in p53 and Noxa on CNS persistence and demyelinating disease; 3) identify potential virus "triggers" of apoptosis by expressing TMEV nonstructural proteins L and 3CD in mammalian cells, and determine whether TMEV replicons in which the capsid proteins are deleted can induce apoptosis; and 4) investigate the mechanism of loss of infectious virus in murine macrophages that is associated with onset of apoptosis.
描述(申请人提供):泰勒氏小鼠脑脊髓炎病毒(TMEV)是一种高度溶解细胞的RNA病毒,可在易感品系的小鼠中产生持续性中枢神经系统(CNS)感染和免疫介导的脱髓鞘。TMEV感染为多发性硬化症提供了相关的实验动物模型。与宿主细胞存活的非溶细胞性RNA病毒的持久性不同,感染细胞死亡的裂解性RNA病毒的持久性需要持续的细胞间传播才能维持感染。在这种情况下,理想情况下病毒持续存在的目标细胞应该是可再生的。这种感染不应该是高效的;然而,病毒特异性的宿主免疫反应可能无论如何都会控制更高效的感染。巨噬细胞是主要的病毒库,为TMEV在小鼠中枢神经系统中的持续存在提供了体外模型。TMEV感染的巨噬细胞发生凋亡并限制病毒的产生(<;10pfu/cell),与其他啮齿动物细胞(包括神经元和少突胶质细胞)的感染相反,在其他啮齿动物细胞中,坏死细胞死亡与高病毒产量(200-500pfu/cell)相关。TMEV感染是诱导小鼠巨噬细胞凋亡所必需的,因为紫外线灭活病毒吸附在细胞表面以启动感染不会诱导细胞凋亡。我们已经证明,TMEV感染通过Bax介导的内在途径诱导细胞凋亡,并严重限制感染病毒在小鼠巨噬细胞中的产生。我们的工作假设是,TMEV诱导的细胞凋亡是一种宿主细胞特异性的机制,提供了一种将病毒传播到未感染的巨噬细胞的手段,吞噬含有感染性病毒的凋亡残留物。为了了解TMEV感染如何触发小鼠巨噬细胞的凋亡并限制感染性病毒的产生,提出了四个具体的目标:1)完成TMEV感染M1-D巨噬细胞过程中涉及内在凋亡途径的上游信号的鉴定,并确定原始巨噬细胞与耐药株和易感株之间的潜在凋亡差异;2)抑制感染小鼠的细胞凋亡,以评估其对TMEV CNS持久性、病毒特异性CD4+T细胞应答和脱髓鞘疾病的影响,并检测P53和NoxA基因缺陷转基因小鼠对CNS持久性和脱髓鞘疾病的影响;3)通过在哺乳动物细胞中表达TMEV非结构蛋白L和3CD来确定潜在的病毒“触发”,并确定缺失衣壳蛋白的TMEV复制子是否能够诱导细胞凋亡;以及4)探讨感染病毒在小鼠巨噬细胞中丢失与启动凋亡相关的机制。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mutation of the Theiler's virus leader protein zinc-finger domain impairs apoptotic activity in murine macrophages.
泰勒病毒前导蛋白锌指结构域的突变会损害小鼠巨噬细胞的凋亡活性。
- DOI:10.1016/j.virusres.2013.09.001
- 发表时间:2013
- 期刊:
- 影响因子:5
- 作者:Son,Kyung-No;Liang,Zhiguo;Lipton,HowardL
- 通讯作者:Lipton,HowardL
Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis.
- DOI:10.1016/j.virusres.2014.10.017
- 发表时间:2015-01-02
- 期刊:
- 影响因子:5
- 作者:Son KN;Lipton HL
- 通讯作者:Lipton HL
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HOWARD Lee LIPTON其他文献
HOWARD Lee LIPTON的其他文献
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{{ truncateString('HOWARD Lee LIPTON', 18)}}的其他基金
Does chronic Theiler's demyelination require viral persistence?
慢性泰勒脱髓鞘症是否需要病毒持续存在?
- 批准号:
8608610 - 财政年份:2012
- 资助金额:
$ 32.48万 - 项目类别:
Does chronic Theiler's demyelination require viral persistence?
慢性泰勒脱髓鞘症是否需要病毒持续存在?
- 批准号:
8423316 - 财政年份:2012
- 资助金额:
$ 32.48万 - 项目类别:
Does chronic Theiler's demyelination require viral persistence?
慢性泰勒脱髓鞘症是否需要病毒持续存在?
- 批准号:
8321170 - 财政年份:2012
- 资助金额:
$ 32.48万 - 项目类别:
Theiler's virus-induced aoptosis: A mechanism for CNS virus persistence
泰勒病毒诱导的细胞凋亡:中枢神经系统病毒持续存在的机制
- 批准号:
7899610 - 财政年份:2010
- 资助金额:
$ 32.48万 - 项目类别:
Theiler's virus-induced aoptosis: A mechanism for CNS virus persistence
泰勒病毒诱导的细胞凋亡:中枢神经系统病毒持续存在的机制
- 批准号:
8016588 - 财政年份:2010
- 资助金额:
$ 32.48万 - 项目类别:
Theiler's virus-induced aoptosis: A mechanism for CNS virus persistence
泰勒病毒诱导的细胞凋亡:中枢神经系统病毒持续存在的机制
- 批准号:
8230762 - 财政年份:2010
- 资助金额:
$ 32.48万 - 项目类别:
Theiler?s virus as a potential cause of Vilyuisk encephalitis
泰勒病毒是 Vilyuisk 脑炎的潜在病因
- 批准号:
7872770 - 财政年份:2009
- 资助金额:
$ 32.48万 - 项目类别:
Identifying a viral cause of Multiple Sclerosis
确定多发性硬化症的病毒原因
- 批准号:
6418535 - 财政年份:2002
- 资助金额:
$ 32.48万 - 项目类别:
Identifying a viral cause of Multiple Sclerosis
确定多发性硬化症的病毒原因
- 批准号:
6762361 - 财政年份:2002
- 资助金额:
$ 32.48万 - 项目类别:
Identifying a viral cause of Multiple Sclerosis
确定多发性硬化症的病毒原因
- 批准号:
7223493 - 财政年份:2002
- 资助金额:
$ 32.48万 - 项目类别:
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