Redox Control of F. tularensis Pathogenesis

病原体衍生的蛋白质、DNA和脂质触发对细菌感染的保护性免疫应答 触发多种激活信号的组件。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sJDecies（ROS/RNS），它们是先天性 免疫反应许多病原体通过以下途径抵抗巨噬细胞（M0）衍生的ROS/RNS的产生： 增强它们对这些物种解毒的能力，或者通过短路导致 他们的生产。病原体抗氧化剂电枢不仅提供直接保护免受氧化攻击， 但可通过限制效应子和细胞因子来干扰宿主细胞信号传导， 和负责保护性免疫的诱导机制。这些独特的功能使我们 建立一个假设，将土拉热弗朗西斯菌（Ft）的有效ROS/RNS清除能力联系起来 SchuS 4限制M0活性的能力。最终结果是创建一个intraM 0环境， 允许这种A类病原体的生长和随后的全身传播。底层 假设F.土拉菌调节细胞内氧化还原环境以控制M0信号传导 和功能我们将：目标1。研究Ft抗氧化防御如何有助于其有效生长， 在体外和体内的细胞内存活。目标2.确定Ft SchuS 4抗氧化剂在 直接或通过FcR靶向调节M0功能。目标3.确定氧化还原敏感信号 在感染FcR靶向的或靶向的M0激酶后负责控制M0激酶信号传导的分子， 非目标性 概述的研究不仅将破译控制Ft毒力的氧化还原触发因子，而且还将与 通过开发工具，使子项目1和2能够评估Ft SchuS 4的贡献， 抗氧化剂分别调节FcR特异性信号和TLR/NLR接合。通过识别 细菌氧化还原--我们可以开发免疫原来优化宿主免疫功能的因素 粘膜接种平台。

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.