Innate Immune Sensing of Microbial Viability

描述(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甚至终身的保护。一次与微生物病原体的接触足以让免疫系统在未来几十年里记住这种病原体。这一基本特性构成了疫苗接种的基础，主要目的是激发长期保护性免疫。有几种好的疫苗，但它们是根据经验得出的，我们仍然不了解使它们如此成功的分子机制。众所周知，以减毒活病原体为基础的疫苗制剂比灭活的疫苗制剂更有效。我们对启动免疫反应的关键因素的了解越来越多，这将我们引向了两个核心角色，即抗原提呈细胞(APC)和模式识别受体(PRRs)。APC捕获微生物病原体，并动员一系列事件，形成针对病原体的有效免疫反应的基础。大多数疫苗制剂中使用的佐剂是一种微生物成分的混合物，可以触发PRR激活并发出免疫反应基因转录启动的信号。到目前为止，我们的研究为区分活细菌和死亡细菌的先天免疫识别提供了强有力的支持。虽然活细菌会触发炎症警觉细胞因子的产生，但死亡细菌无法做到这一点。因此，活细菌和死亡细菌中存在的一种与微生物活性相关的成分似乎是APC唯一识别的。识别该组件需要TLR信令适配器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)确定活细菌激活胞质感染传感器的能力。2)描述携带活细菌和死亡细菌的细胞内隔间的性质。与公共卫生相关：这项提议旨在了解一种新的免疫识别模式的基础，即对微生物生存能力的先天感知。我们的目标是识别那些由活的而不是死亡的病原体具体触发的通路。我们的工作将有助于为新一代疫苗奠定基础，这些疫苗有望提供保护，抵御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.