Mechanisms coordinating the local and systemic resistance to pathogens

摘要：协调局部和系统对病原体的抗性的机制。 保护宿主免受病原体侵害，以确保动态平衡和健康，需要多个 单元类型。许多通过特定组织入口进入宿主的病原体通常可以传播到多个 随着时间的推移会对组织造成严重损害，对其他宿主器官造成严重损害。先天细胞和适应性细胞 免疫系统对初始感染和播散性感染做出反应，以建立强大的防御系统 病原体攻击的两个阶段。重要的是，在某些情况下，传播延迟于初次感染。 直观地说，如果播散性感染的最终部位在免疫上做好了准备，那么 从潜在的病原菌生长的潜在感染部位，宿主就能更好地控制系统 疾病。值得注意的是，导致这一提议的初步数据表明，这种机制在很长一段时间内 局部树突状细胞(DC)和远端基质细胞之间的距离协调是通过迄今 未被认可的异二聚体细胞因子IL-12的产生途径。我们假设病原体激活了 原始感染部位的树突状细胞分泌惰性的IL-12p40单体，这些单体循环到远处的器官， 与基质细胞局部释放的IL-12p35结合，定制组织特异性预期免疫。这么长的时间- IL-12惰性亚基在组织内的距离组合使单个部位不仅启动了 免疫细胞在该微环境中预测潜在感染，但也微调免疫在 组织特异性方式(例如，通过释放IL-23p19蛋白而不是IL-12p35，这将导致局部 IL-23的组装和最终扩增17型免疫而不是1型免疫)。 在这项建议中，我们评估了分子，细胞和系统水平的机制这一假说使用 三个独立且收敛的特定目标(SA)。 SA1：研究两个亚基释放的细胞和分子机制(P40和P35) 以及促进它们在组织水平上组装成IL-12的原理。产生P40的DC子集， 有利于单体释放和允许组织保留的适应性的选择性机制将被剖析。 启动P35释放的组织信号以及对P19的意义(P40-负责IL-23的伙伴)将 也要接受评估。 SA2：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有反应的免疫细胞和免疫持续时间 由此产生的修改将在免疫接种和传染病挑战的背景下进行衡量。 SA3：通过使用生理性混合感染来定义免疫预感的系统性后果 模特。能够改变局部和系统P40的生物体被认为是我们宿主微生物的天然组成部分 两性关系。我们将测量在细菌存在的情况下对急性感染的反应，确定影响 本地IL-12以了解初级和远端部位的免疫如何协调以实现最佳的宿主防御 对多个病原体并行传播。 综上所述，我们预计这些研究将通过揭示细胞和分子的 寄主防御中关键的组织间沟通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疗法，以提高组织特异性免疫。 在远程地点接种疫苗，减少局部感染的系统性免疫病理学，并改善 寄主抵抗病原体的传播或定植。

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.