Role of viral BCI-2 mediated anti-apoptosis and-autophagy
病毒 BCI-2 介导的抗凋亡和自噬的作用
基本信息
- 批准号:8893863
- 负责人:
- 金额:$ 47.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-15 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAntigen PresentationApoptosisApoptoticAutophagocytosisAutophagosomeBacterial Artificial ChromosomesBiochemicalBiogenesisBiologicalBiologyCD19 geneCD34 geneCancer EtiologyCellsCellular biologyEatingEnzymesFigs - dietaryGenesGenomeGoalsHealthHematopoietic stem cellsHerpesviridaeHerpesviridae InfectionsHumanHuman Herpesvirus 8ImmuneImmune responseImmunityInfectionInvadedLifeMediatingMusMutateNatural ImmunityOrganellesOrganismOutcomePathogenesisPathway interactionsProcessProteinsRecombinantsRoleSignal TransductionStagingTestingVacuumVesicleVial deviceViralViruscombatgenetic manipulationgenome editingin vivoinhibition of autophagyinnovationkillingsmouse modelnovelpathogenprotein complexrecombinant virus
项目摘要
DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV), an important human pathogen accounting for a large percentage of virally caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish a life-long persistent infection. Autophagy pathway consists of four distinct stages of autophagosome biogenesis-induction, vesicle nucleation, vesicle elongation, and vesicle maturation- by forming specific protein complexes. Our study has discovered a novel KSHV-mediated comprehensive inhibition of autophagy pathway where KSHV remarkably confers tight suppression of the autophagy by targeting each step of its signal transduction: by vBcl-2 in vesicle nucleation, by vFLIP in vesicle elongation, and by K7 in vesicle maturation. Specifically, the vBcl-2, vFLIP, and K7 not only possess anti- apoptotic activities but also serve as anti-autophagy molecules via their interactions with the Beclin1, the Atg3 E2 enzyme, and the Rubicon, respectively, which contributes to the establishment of viral persistency. This also indicates how important autophagy is as part of host immune responses against pathogens. Furthermore, we have recently developed an "infectious" KSHV bacterial artificial chromosome (BAC16) and TALEN- mediated genome editing that allows the efficient genetic manipulation of KSHV genome as well as host genome to study viral persistence and pathogenesis. Thus, the goal of this study is two-fold: firstly, to identify the specific mechanisms of how viral anti-autophagy proteins target and suppress autophagy- mediated host immunity and secondly, to test whether the suppression of autophagy-mediated host immunity is necessary for in vivo KSHV persistent infection. Despite previous extensive cell biology and biochemical studies, the detailed in vivo biological evidences of vBcl-2- and K7-mediated immune evasion for viral persistence are still elusive. In this proposal, we will attempt to define in vivo roles of the vBc-2 and K7 in vial persistence. Specifically, by utilizing in NOD/SCID IL2Rgamma-/- "humanized" mouse model, we will test whether the loss of vBcl-2 and/or K7 genes from the KSHV genome affects the establishment of viral persistence and how critical autophagy is as a host immune determinant to control the in vivo KSHV latency. This proposal is highly innovative and its successful outcome should significantly impact our understanding of KSHV biology.
描述(由申请人提供):卡波西肉瘤相关疱疹病毒(KSHV)是一种重要的人类病原体,占全球病毒引起的癌症的很大比例,它已经进化出多种策略来逃避宿主免疫反应,从而建立终身持续感染。自噬途径通过形成特定的蛋白质复合物,包括自噬体生物发生的四个不同阶段——诱导、囊泡成核、囊泡延伸和囊泡成熟。我们的研究发现了一种新的KSHV介导的自噬全面抑制途径,其中KSHV通过靶向其信号转导的每个步骤显著地给予自噬严格抑制:通过囊泡成核中的vBcl-2,囊泡延伸中的vFLIP和囊泡成熟中的K7。具体来说,vBcl-2、vFLIP和K7不仅具有抗凋亡活性,而且还分别通过与Beclin1、Atg3 E2酶和Rubicon酶的相互作用作为抗自噬分子,这有助于建立病毒的持久性。这也表明自噬作为宿主对抗病原体的免疫反应的一部分是多么重要。此外,我们最近开发了一种“感染性”KSHV细菌人工染色体(BAC16)和TALEN介导的基因组编辑,允许对KSHV基因组和宿主基因组进行有效的遗传操作,以研究病毒的持久性和发病机制。因此,本研究的目的是双重的:首先,确定病毒抗自噬蛋白如何靶向和抑制自噬介导的宿主免疫的具体机制;其次,测试抑制自噬介导的宿主免疫是否对体内KSHV持续感染是必要的。尽管之前进行了广泛的细胞生物学和生化研究,但vcl -2和k7介导的免疫逃避对病毒持久性的详细体内生物学证据仍然难以捉摸。在本提案中,我们将尝试定义vBc-2和K7在小瓶持久性中的体内作用。具体来说,通过NOD/SCID IL2Rgamma-/-“人源化”小鼠模型,我们将测试从KSHV基因组中丢失vBcl-2和/或K7基因是否会影响病毒持久性的建立,以及自噬作为宿主免疫决定因素在控制体内KSHV潜伏期中的关键作用。这一建议极具创新性,其成功的结果将显著影响我们对KSHV生物学的理解。
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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Jae U Jung其他文献
Signaling Role of Viral Protein Motif and Its Application in CAR T Cell Therapy
- DOI:
10.1182/blood-2023-186305 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Kunho Chung;Wooram Jung;Jae U Jung;J. Joseph Melenhorst - 通讯作者:
J. Joseph Melenhorst
Jae U Jung的其他文献
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{{ truncateString('Jae U Jung', 18)}}的其他基金
Infant Immunologic and Neurologic Development following Maternal Infection in Pregnancy during Recent Epidemics
近期流行病期间妊娠期感染后婴儿的免疫和神经系统发育
- 批准号:
10784250 - 财政年份:2023
- 资助金额:
$ 47.76万 - 项目类别:
Reassortment of Bunyavirus in ticks and animal models
蜱和动物模型中布尼亚病毒的重排
- 批准号:
10512873 - 财政年份:2022
- 资助金额:
$ 47.76万 - 项目类别:
Reassortment of Bunyavirus in ticks and animal models
蜱和动物模型中布尼亚病毒的重排
- 批准号:
10686796 - 财政年份:2022
- 资助金额:
$ 47.76万 - 项目类别:
Structural analysis and therapeutic nanobody development of KSHV G-protein coupled receptor
KSHV G 蛋白偶联受体的结构分析和治疗性纳米抗体开发
- 批准号:
10413218 - 财政年份:2020
- 资助金额:
$ 47.76万 - 项目类别:
KSHVmediated regulation of proline metabolism
KSHV介导的脯氨酸代谢调节
- 批准号:
10293612 - 财政年份:2020
- 资助金额:
$ 47.76万 - 项目类别:
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