Innate Immune Sensing of Microbial Viability

描述（由申请人提供）：对于大多数感染，免疫系统对许多微生物病原体提供长期，有时是终身保护。与微生物病原体的一次接触足以让免疫系统在未来几十年内记住这种病原体。这一基本特性构成了疫苗接种的基础，其主要目的是引发长期保护性免疫。有几种很好的疫苗，但它们都是经验性的，我们仍然不了解使它们如此成功的分子机制。众所周知，基于减毒活病原体的疫苗制剂比灭活制剂更有效。我们对免疫应答启动中所涉及的关键要素的认识不断增加，这将我们指向两个核心参与者，抗原呈递细胞（APC）和模式识别受体（PRR）。APC捕获微生物病原体并动员形成针对病原体的有效免疫应答的基础的一系列事件。大多数疫苗制剂中使用的佐剂是微生物组分的混合物，其触发PRR活化并发出免疫应答基因转录起始的信号。到目前为止，我们的研究为活细菌和死细菌的差异先天免疫识别提供了强有力的支持。虽然活细菌触发炎症警报细胞因子的产生，但死细菌不能这样做。因此，差异存在于活的和死的细菌，并与微生物的活力，似乎是唯一的APC识别的组件。识别该组分需要TLR信号转导衔接子MyD88。我们假设先天免疫系统能够区分活的和死的病原体，并相应地动员不同的信号通路和细胞免疫反应。由活细菌引发的独特反应可能是长期免疫的关键。我们的具体目标是：1）确定活细菌激活感染的胞质传感器的能力。2)表征携带活菌与死菌的细胞内隔室的性质。公共卫生相关性：该提案旨在了解一种新的免疫识别模式的基础，即微生物活力的先天传感。我们的目标是确定那些由活的而不是死的病原体特异性触发的途径。我们的工作将有助于为新一代疫苗奠定基础，这些疫苗有望保护人们免受许多新的和现有的微生物威胁。

DESCRIPTION (provided by applicant): For most infections, the immune system confers long-term and sometimes life-long protection against many microbial pathogens. One encounter with a microbial pathogen is sufficient to allow the immune system to remember this pathogen for decades to come. This fundamental property forms the basis for vaccination with the main purpose of eliciting long-term protective immunity. Several good vaccines exist, but they were derived quite empirically and we still do not understand the molecular mechanisms that make them so successful. Vaccine preparations based on live attenuated pathogens are notoriously more effective than killed preparations. Our increasing knowledge of the critical elements involved in the initiation of immune responses points us towards two central players, antigen presenting cells (APCs) and pattern recognition receptors (PRRs). APCs capture microbial pathogens and mobilize a sequence of events that forms the basis for mounting an effective immune response against the pathogen. Adjuvants, used in most vaccine preparations, are a mixture of microbial components that trigger PRR activation and signal the transcriptional initiation of immune response genes. Our studies so far provide strong support for differential innate immune recognition of live and dead bacteria. While live bacteria trigger production of inflammatory alert cytokines, dead bacteria fail to do so. Thus, a component differentially present in live and dead bacteria, and which correlates with microbial viability, appears to be uniquely recognized by APCs. Recognition of this component requires the TLR signaling adaptor MyD88. We hypothesize that the innate immune system is capable of discriminating between live and dead pathogens, and accordingly mobilizes distinct signaling pathways and cellular immune responses. The unique responses triggered by live bacteria may hold the key to long-term immunity. Our specific aims are designed to: 1) Determine the ability of live bacteria to activate cytosolic sensors of infection. 2) Characterize the nature of intracellular compartments carrying live versus dead bacteria. PUBLIC HEALTH RELEVANCE: This proposal is aimed to understand the basis for a new mode of immune recognition, the innate sensing of microbial viability. We aim to identify those pathways specifically triggered by live and not dead pathogens. Our work will help set the stage for novel generations of vaccines that hold the promise of conferring protection against many new and existing microbial threats.