Mechanisms coordinating the local and systemic resistance to pathogens

协调局部和全身对病原体的抵抗力的机制

基本信息

  • 批准号:
    10587868
  • 负责人:
  • 金额:
    $ 60.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-11-02 至 2027-10-31
  • 项目状态:
    未结题

项目摘要

Summary: Mechanisms coordinating the local and systemic resistance to pathogens. Defending a host against pathogens to ensure homeostasis and health requires the coordinated effort of multiple cell types. Many pathogens that enter the host via a specific tissue portal can often disseminate to multiple tissues over time and cause significant damage to additional host organs. Cells of the innate and adaptive immune system respond to the initial infection as well as disseminated infection to mount robust defense against both phases of pathogen attack. Importantly, in some cases, dissemination is delayed from the primary infection. Intuitively, if the eventual sites of disseminated infection were immunologically prepared to expect the arrival of potential infection from the primary site of pathogen growth, the host would be better able to control systemic disease. Significantly, the preliminary data leading to this proposal suggests that such a mechanism for long range coordination between local dendritic cells (DC) and distant stromal cells operates via a hitherto unappreciated pathway for making the heterodimeric cytokine IL-12. We hypothesize that pathogen-activated Dendritic Cells at the original site of infection secrete inert IL-12p40 monomers which circulate to distant organs, combine with IL-12p35 released locally by stromal cells to tailor tissue-specific anticipatory immunity. This long- distance combination of inert subunits of IL-12 within tissue niches allows individual sites to not only prime the immune cells in that microenvironment in anticipation of potential infection, but also fine-tune immunity in a tissue-specific fashion (e.g. by releasing the protein IL-23p19 instead of IL-12p35, which would lead to the local assembly of IL-23 and eventual amplification of type17 immunity instead of type1). In this proposal, we evaluate the molecular, cellular and systems level mechanisms of this hypothesis using three independent and convergent Specific Aims (SA). SA1: examines the cellular and molecular mechanisms underlying the release of both subunits (P40 and P35) as well as the principles which facilitate their tissue-level assembly into IL-12. DC subsets producing P40, selective mechanisms favoring monomer release and adaptations allowing tissue retention will be dissected. Tissue signals initiating P35 release as well as significance for P19 (the P40-partner responsible for IL-23) will also be evaluated. SA2: studies how host defense is facilitated by the innovative concept of Immunological premonition in tissues at a cellular level. Immune cells that respond to locally assembled IL-12 and the duration of the immune modifications resulting from this will be measured in the context of immunizations as well as infectious challenge. SA3: defines the systemic consequences of immunological premonition by using a physiological co-infection model. Organisms that can modify local vs systemic P40 are expected to be natural part of our host-microbe relationships. We will measure responses to acute infections in the presence of bacteria with defined impact on local IL-12 to understand how immunity at primary and distal sites are coordinated to effect optimal host defense to multiple pathogens in parallel. Taken together, we expect these studies to be transformative by revealing the cellular and molecular mechanisms underlying a critical inter-tissue communication and coordination axis in host defense. Future studies can develop clinical therapeutics targeting these pathways to improve tissue-specific immunity from vaccines administered at distant sites, reducing systemic immunopathology from local infections, and improving host resistance to pathogen dissemination or colonization.
摘要:协调对病原体的局部和全身抗性的机制。 保护宿主免受病原体的侵害以确保体内平衡和健康需要多个免疫系统的协调努力。 细胞类型。许多病原体通过特定的组织入口进入宿主,通常可以传播到多个组织。 随着时间的推移组织,并导致其他宿主器官的严重损害。先天性和适应性细胞 免疫系统对初始感染以及传播性感染做出反应,以建立强大的防御, 病原体攻击的两个阶段重要的是,在某些情况下,传播从原发感染延迟。 直觉上,如果最终的播散性感染部位在免疫学上做好了准备, 从病原体生长的主要部位的潜在感染,宿主将能够更好地控制系统性 疾病值得注意的是,导致这一建议的初步数据表明,这种机制长期以来 局部树突状细胞(DC)和远端基质细胞之间的范围协调通过迄今为止的 这是一种不受重视的产生异源二聚体细胞因子IL-12的途径。我们假设病原体激活 在感染的原始部位的树突状细胞分泌惰性IL-12 p40单体,其循环到远端器官, 联合收割机与基质细胞局部释放的IL-12 p35结合,以定制组织特异性预期免疫。这么久- IL-12的惰性亚基在组织小生境内的距离组合允许各个位点不仅引发细胞内的免疫反应, 免疫细胞在微环境中预测潜在感染,而且还在 组织特异性方式(例如通过释放蛋白IL-23 p19而不是IL-12 p35,这将导致局部免疫缺陷)。 IL-23的组装和最终17型免疫而不是1型免疫的放大)。 在这个建议中,我们评估了这一假设的分子,细胞和系统水平的机制,使用 三个相互独立又相互融合的具体目标(SA)。 SA 1:检查两种亚基(P40和P35)释放的细胞和分子机制 以及促进它们在组织水平组装成IL-12的原理。产生P40的DC亚群, 将剖析有利于单体释放和允许组织保留的适应的选择性机制。 启动P35释放的组织信号以及P19(负责IL-23的P40伴侣)的意义将 也被评价。 SA 2:研究组织中免疫预感的创新概念如何促进宿主防御 在细胞水平上。对局部组装的IL-12应答的免疫细胞和免疫持续时间 由此产生的修饰将在免疫接种以及感染性攻击的情况下测量。 SA 3:通过使用生理性共感染定义免疫预感的全身性后果 模型能够改变局部与系统性P40的生物体有望成为我们宿主微生物的天然组成部分 关系。我们将测量在细菌存在下对急性感染的反应, 局部IL-12,以了解原发部位和远端部位的免疫如何协调以实现最佳宿主防御 同时感染多种病原体 总的来说,我们希望这些研究能够通过揭示细胞和分子的变化来改变。 在宿主防御中,关键的组织间通信和协调轴的潜在机制。未来 研究可以开发针对这些途径的临床治疗方法,以提高组织特异性免疫力, 在远处接种疫苗,减少局部感染引起的全身免疫病理学, 宿主对病原体传播或定殖的抵抗力。

项目成果

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Nevil John Singh其他文献

Nevil John Singh的其他文献

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{{ truncateString('Nevil John Singh', 18)}}的其他基金

An IL-12 family heterodimer that regulates IL-4 production by T cells
调节 T 细胞产生 IL-4 的 IL-12 家族异二聚体
  • 批准号:
    10495254
  • 财政年份:
    2021
  • 资助金额:
    $ 60.91万
  • 项目类别:
An IL-12 family heterodimer that regulates IL-4 production by T cells
调节 T 细胞产生 IL-4 的 IL-12 家族异二聚体
  • 批准号:
    10353589
  • 财政年份:
    2021
  • 资助金额:
    $ 60.91万
  • 项目类别:
Mechanisms maintaining the self-awareness of peripheral T cells
维持外周T细胞自我意识的机制
  • 批准号:
    9979091
  • 财政年份:
    2020
  • 资助金额:
    $ 60.91万
  • 项目类别:
Mechanisms maintaining the self-awareness of peripheral T cells
维持外周T细胞自我意识的机制
  • 批准号:
    10242775
  • 财政年份:
    2020
  • 资助金额:
    $ 60.91万
  • 项目类别:
Modifying T Cell Responses by Combinatorial Targeting of Negative regulators
通过负调节剂的组合靶向改变 T 细胞反应
  • 批准号:
    8874742
  • 财政年份:
    2014
  • 资助金额:
    $ 60.91万
  • 项目类别:
Role of sub-activation-threshold TCR interactions in maintaining T cell memory
亚激活阈值 TCR 相互作用在维持 T 细胞记忆中的作用
  • 批准号:
    8975607
  • 财政年份:
    2014
  • 资助金额:
    $ 60.91万
  • 项目类别:
Role of sub-activation-threshold TCR interactions in maintaining T cell memory
亚激活阈值 TCR 相互作用在维持 T 细胞记忆中的作用
  • 批准号:
    8818536
  • 财政年份:
    2014
  • 资助金额:
    $ 60.91万
  • 项目类别:

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