Redox Control of F. tularensis Pathogenesis

对细菌感染的保护性免疫反应是由病原体衍生的蛋白质、DNA和脂质触发的 触发各种激活信号阵列的组件。一旦激活，宿主炎症细胞 通过产生炎性细胞因子和产生 活性氧和氮氧化物(ROS/RNS)是天然的细胞毒性效应分子 免疫反应。许多病原体通过以下途径抵抗巨噬细胞(M0)来源的ROS/RNS的产生 增强它们对这些物种的解毒能力，或者通过短路导致 他们的作品。病原体抗氧化剂电甲不仅提供直接保护免受氧化攻击， 但可能会干扰宿主细胞的信号传递，从而通过限制两个效应器来促进其细胞内的生存 以及负责保护性免疫的诱导机制。这些独特的功能使我们能够 提出一个假设，将土拉方杆菌(Ft)有效清除ROS/RNS的能力联系起来 SchuS4具有限制M0活性的能力。最终结果是创建一个内部M0环境，即 允许这种A类病原体的生长和随后的系统性传播。内幕消息 假说是图拉藻调节细胞内的氧化还原环境以控制M0信号。 和功能。我们将：目标1。研究Ft抗氧化剂防御如何促进其有效生长和 在体外和体内的细胞内存活。目的2.确定Ft SchuS4抗氧化剂在 直接或通过FCR调整M0功能。目的3.确定氧化还原敏感信号 在感染FCR靶向或FCR时负责控制M0激酶信号的分子 非目标堡垒 概述的研究不仅将破译控制Ft毒力的氧化还原触发因素，而且还将与 通过开发工具，使子项目1和2能够评估Ft SchuS4的贡献，从而总体P01 抗氧化剂分别在调节FCR特异性信号和TLR/NLR结合中起作用。通过识别 细菌氧化还原-调节宿主免疫功能的因素我们可以开发免疫原来优化 黏膜疫苗接种平台。

Protective immune responses to bacterial infection are triggered by pathogen derived proteins, DNA and lipid components which trigger a diverse array of activation signals. Upon activation, the host inflammatory cells respond to the pathogen-derived insult by the production of inflammatory cytokines and the generation of both reactive oxygen and nitrogen sJDecies (ROS/RNS) that are the cytotoxic effector molecules of the innate immune response. Many pathogens resist the production of macrophage (M0)-derived ROS/RNS by augmenting their ability to detoxify these species or by short circuiting the signaling pathways that lead to their production. A pathogens antioxidant armature not only provides direct protection from oxidative attack, but may interfere with host cell signaling that facilitates its intracellular survival by restricting both the effector and inductive mechanisms responsible for protective immunity. These unique features have led us to develop a hypothesis that links the efficient ROS/RNS scavenging capacity of Francisella tularensis (Ft) SchuS4 to its ability to restrict M0 activity. The end result is the creation of an intraM0 environment that is permissive for growth and subsequent systemic dissemination of this category A pathogen. The underiying hypothesis is that F. tularensis modulates the intracellular redox environment to control M0 signaling and function. We will: Aim 1. Investigate how Ft antioxidant defenses contribute to its effective growth and intracellular survival both in vitro and in vivo. Aim 2. Determine the role of Ft SchuS4 antioxidants in regulating M0 function directly or when targeted via FcR. Aim 3. Determine the redox-sensitive signaling molecules that are responsible for the control of M0 kinase signaling upon infection with FcR-targeted or non-targeted Ft. The studies outlined will not only decipher the redox-triggers that control Ft virulence but also synergize with the overall P01 by developing tools that enable subprojects 1 & 2 to evaluate the contribution Ft SchuS4 antioxidants in modulating FcR-specific signals, and TLR/NLR engagement, respectively. By identifying the bacterial redox-factors that mocjulate host immune function we can develop immunogens to optimize mucosal vaccination platform.