Live Imaging of Immunity to M. tuberculosis
结核分枝杆菌免疫实时成像
基本信息
- 批准号:10326395
- 负责人:
- 金额:$ 10.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-06 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Antigen PresentationAntigensBacteriaC57BL/6 MouseCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCaliforniaCell CommunicationCellsChronicCommunicable DiseasesDevelopmentDistantEffectivenessEnvironmentEventFailureFrequenciesGoalsGranulomaHIVHumanImageImmuneImmunityInfectionKnowledgeLightLungLymphocyteLymphocyte antigenLymphoid CellMechanicsMedicineModelingMolecularMusMycobacterium tuberculosisMyeloid CellsNaturePeptide/MHC ComplexPhenotypePlayPositioning AttributeReagentReporterResearchRoleSan FranciscoSignal TransductionSiteStructure of parenchyma of lungSystemT cell responseT-Cell DevelopmentT-LymphocyteTestingTissuesTuberculosisTuberculosis VaccinesUniversitiesUp-RegulationVaccinesWorkadaptive immune responseantigen-specific T cellsbiosafety level 3 facilitychemokine receptorchronic infectiondesignexperimental studyfollow-upimmune checkpointin vivoinnovationinsightintravital imagingintravital microscopymigrationmultiphoton microscopynonhuman primatepathogenpredictive modelingreceptor expressionreceptor functionresponsetooltuberculosis immunityvaccine trial
项目摘要
Project Summary
Tuberculosis (TB), caused by the bacterium, Mycobacterium tuberculosis, kills more humans every year than
does any other infectious disease, including HIV. Among the obstacles to eliminating TB is the lack of a
sufficiently-efficacious vaccine. Despite strong evidence for essential roles of CD4 T cells in TB immunity,
naturally-occurring T cell responses do not reliably eliminate the pathogen in TB, and we do not fully understand
the mechanisms that limit the effectiveness of CD4 T cell responses to M. tuberculosis. In earlier work, we
discovered that for optimal immune control, CD4 T cells must directly recognize and make intermolecular
contacts with M. tuberculosis-infected cells at the site of infection in the lungs. In light of this requirement for
intimate contact, we and others have found (in mice, nonhuman primates, and humans) that CD4 T cells are
located at the periphery of granulomas, rather than in the core where infected cells reside. We therefore
hypothesize that a major mechanism limiting immunity to TB is the failure of CD4 T cells to contact and engage
with infected cells, and that overcoming this failure will increase the efficacy of T cell immunity to TB. Several
potential mechanisms can explain the spatial separation of M. tuberculosis-infected cells and CD4 T cells in vivo,
yet these are not amenable to analysis using fixed, static images or cells removed from the granuloma
environment. Therefore, in this project, we propose to combine a unique multiphoton microscopy system for
intravital imaging, contained in a Biosafety Level 3 facility at the IPBS in Toulouse, with unique reporter mice and
M. tuberculosis strains developed and characterized at UCSF, to characterize interactions of antigen-specific
CD4 T cells with M. tuberculosis-infected and bystander cells in the lungs of live mice. The combination of these
innovative experimental systems allows us to test specific hypotheses that can account for the spatial and
functional separation of CD4 T cells and M. tuberculosis-infected cells in the lungs. The knowledge gained from
these studies will be used: 1) to inform design of experiments to define the molecular mechanisms that restrict
CD4 T cell interactions with M. tuberculosis-infected cells in vivo; 2) to provide the basis for studies comparing
distinct candidate TB vaccines, to determine which of them promote development of T cells that optimally access
M. tuberculosis-infected cells in granuloma cores. In additional experiments, we will extend recent findings
indicating important roles for innate lymphoid cells (ILC) in protective immunity to TB. Specifically, we will follow
up on findings that type 2 ILC (ILC2) undergo dramatic phenotypic transformations to ILC1-like cells in vivo in
response to M. tuberculosis infection, by live imaging of the interactions of ILC2 and ILC1-like cells with M.
tuberculosis-infected cells and with CD4 T cells, during the initial and the chronic stages of infection. Our studies
have high potential to provide valuable insights and new paradigms of immunity to TB, with the goal of informing
development of efficacious vaccines and host-directed therapies.
项目摘要
结核病(TB),由结核分枝杆菌引起,每年杀死的人比
包括艾滋病在内的任何其他传染病。消除结核病的障碍之一是缺乏一个
非常有效的疫苗。尽管有强有力的证据表明CD 4 T细胞在结核病免疫中起着重要作用,
自然发生的T细胞反应并不能可靠地消除结核病中的病原体,
限制CD 4 T细胞对M.结核在早期的工作中,我们
发现,为了获得最佳的免疫控制,CD 4 T细胞必须直接识别并制造分子间
与M的联系肺内感染部位的结核感染细胞。根据这一要求,
亲密接触,我们和其他人已经发现(在小鼠,非人灵长类动物和人类),CD 4 T细胞是
位于肉芽肿的外围,而不是感染细胞所在的核心。因此我们
假设限制对结核病免疫的主要机制是CD 4 T细胞无法接触和参与
与受感染的细胞,克服这一失败将增加T细胞免疫结核病的功效。几
可能的机制可以解释M的空间分离。结核感染的细胞和体内的CD 4 T细胞,
但是这些不适于使用固定的、静态的图像或从肉芽肿中取出的细胞进行分析
环境因此,在这个项目中,我们建议将联合收割机与一个独特的多光子显微镜系统相结合,
活体成像,包含在图卢兹IPBS的生物安全3级设施中,使用独特的报告小鼠,
M.加州大学旧金山分校开发并表征结核菌株,以表征抗原特异性相互作用
CD 4 T细胞与M.肺结核感染和旁观者细胞在活小鼠的肺。结合这些
创新的实验系统使我们能够测试特定的假设,可以解释空间和
CD 4 T细胞和M.肺里的结核感染细胞知识来自于
这些研究将用于:1)为实验设计提供信息,以确定限制
CD 4 T细胞与M.结核感染细胞在体内; 2)为研究比较
不同的候选结核病疫苗,以确定它们中的哪一种促进T细胞的发育,
M.肉芽肿核心中的结核感染细胞。在另外的实验中,我们将扩展最近的发现,
表明先天性淋巴样细胞(ILC)在对TB的保护性免疫中的重要作用。具体来说,我们将遵循
2型ILC(ILC 2)在体内经历了向ILC 1样细胞的显著表型转化,
回应M。结核感染,通过ILC 2和ILC 1样细胞与M.
结核感染的细胞和CD 4 T细胞,在感染的初始和慢性阶段。我们的研究
具有提供有价值的见解和新的结核病免疫范例的巨大潜力,其目标是提供信息,
开发有效的疫苗和针对宿主的疗法。
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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Joel D. Ernst其他文献
The immunological life cycle of tuberculosis
结核病的免疫生命周期
- DOI:
10.1038/nri3259 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:60.900
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Transfer of phagocytosed particles to the parasitophorous vacuole of Leishmania mexicana is a transient phenomenon preceding the acquisition of annexin I by the phagosome.
吞噬颗粒向墨西哥利什曼原虫寄生液泡的转移是吞噬体获得膜联蛋白 I 之前的短暂现象。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:4
- 作者:
Helen L. Collins;Ulrich E. Schaible;Joel D. Ernst;David G. Russell - 通讯作者:
David G. Russell
Editorial response: variation in clinical and immune responses to bacille Calmette-Guérin--implications for an improved tuberculosis vaccine.
编辑回应:卡介苗临床和免疫反应的变化——对改进结核病疫苗的影响。
- DOI:
10.1086/515202 - 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Antibody-Fab and -Fc features promote emMycobacterium tuberculosis/em restriction
抗体的 Fab 和 Fc 特征促进了对结核分枝杆菌的限制。
- DOI:
10.1016/j.immuni.2025.05.004 - 发表时间:
2025-06-10 - 期刊:
- 影响因子:26.300
- 作者:
Patricia S. Grace;Joshua M. Peters;Jaimie Sixsmith;Richard Lu;Edward B. Irvine;Corinne Luedeman;Brooke A. Fenderson;Andrew Vickers;Matthew D. Slein;Tanya McKitrick;Mo-Hui Wei;Richard D. Cummings;Aaron Wallace;Lisa A. Cavacini;Alok Choudhary;Megan K. Proulx;Christopher Sundling;Gunilla Källenius;Rajko Reljic;Joel D. Ernst;Galit Alter - 通讯作者:
Galit Alter
Finding and filling the knowledge gaps in mechanisms of T cell-mediated TB immunity to inform vaccine design
寻找并填补 T 细胞介导的结核病免疫机制中的知识空白,为疫苗设计提供信息
- DOI:
10.1038/s41577-025-01192-z - 发表时间:
2025-06-13 - 期刊:
- 影响因子:60.900
- 作者:
Emma Lefrançais;Denis Hudrisier;Olivier Neyrolles;Samuel M. Behar;Joel D. Ernst - 通讯作者:
Joel D. Ernst
Joel D. Ernst的其他文献
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{{ truncateString('Joel D. Ernst', 18)}}的其他基金
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 10.1万 - 项目类别:
Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
- 批准号:
10593978 - 财政年份:2022
- 资助金额:
$ 10.1万 - 项目类别:
Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
- 批准号:
10358264 - 财政年份:2022
- 资助金额:
$ 10.1万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10005738 - 财政年份:2020
- 资助金额:
$ 10.1万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10194362 - 财政年份:2020
- 资助金额:
$ 10.1万 - 项目类别:
Antigen export in M. tuberculosis evasion of CD4 T cells
结核分枝杆菌逃避 CD4 T 细胞的抗原输出
- 批准号:
9318402 - 财政年份:2016
- 资助金额:
$ 10.1万 - 项目类别:
Epitope-specific T cell activation to complement TB immunity and vaccine efficacy
表位特异性 T 细胞激活可补充结核病免疫和疫苗功效
- 批准号:
8867688 - 财政年份:2014
- 资助金额:
$ 10.1万 - 项目类别:
Initiation of the Immune Response to M. tuberculosis
对结核分枝杆菌的免疫反应的启动
- 批准号:
8678398 - 财政年份:2014
- 资助金额:
$ 10.1万 - 项目类别:
Mycobacterium tuberculosis evasion of CD4+ T cells in vivo
体内结核分枝杆菌逃避 CD4 T 细胞
- 批准号:
8678383 - 财政年份:2013
- 资助金额:
$ 10.1万 - 项目类别:
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