Modulation of macrophage function by Francisella tularensis

描述（由申请人提供）：土拉菌弗朗西斯菌（Ft） SchuS4菌株是土拉菌病的病原体，是生物战和生物恐怖主义中最致命的潜在病原体之一。Ft的一个关键特征是它能够抑制或破坏主要参与先天免疫防御的细胞的功能。最近的研究表明，Ft感染导致这种细菌在宿主体内快速复制。尽管细菌数量激增，但巨噬细胞和中性粒细胞的激活明显受到抑制。此外，Ft通过阻断信号转导通路，对促炎细胞因子的诱导具有深远的抑制作用。然而，负责这种免疫颠覆的ft编码因子在很大程度上仍未确定。该A类病原体未发现与毒力相关的分泌系统、分泌蛋白或毒素。我们的初步研究表明，Ft具有独特的破坏先天免疫的机制。我们观察到，Ft的抗氧化剂不仅可以清除因感染而产生的活性氧和活性氮（ROS/RNS），还可以干扰信号通路，抑制促炎细胞因子和巨噬细胞的激活。基于这些观察结果，我们提出了一种假设，将Ft强大的氧化剂清除能力与其抑制巨噬细胞功能的能力联系起来。该应用的中心假设是“Ft改变氧化还原敏感信号成分的抗氧化防御以抑制巨噬细胞的杀微生物活性”。该应用旨在了解Ft的毒力机制，该机制为其巨噬细胞内存活、生长和毒力创造了一个允许的环境。我们建议通过以下具体目标来检验这一假设：目的1。探讨Ft SchuS4抗氧化剂如何破坏巨噬细胞的杀微生物活性。目标2。确定控制NF-kB信号和促炎细胞因子反应的氧化还原敏感成分。目的3：建立Ft抗氧化剂抑制nod样受体（NLR）介导的信号传导和抑制杀微生物活性的机制。拟议的研究与公共卫生有关，因为Ft作为生物恐怖主义媒介的重新出现构成了严重的公共卫生威胁。了解既抑制免疫又促进发病机制的弗朗西斯菌因子可能会导致土拉菌病的治疗和更安全、更有效的疫苗。

DESCRIPTION (provided by applicant): Francisella tularensis (Ft) SchuS4 strain, the causative agent of tularemia, is amongst the most deadly potential agents of biological warfare and bioterrorism. One critical characteristic of Ft is its ability to dampen or subvert the functions of the cells primarily involved in innate immune defenses. Recent studies have shown that Ft infection leads to rapid replication of this bacterium in the host. Despite an explosive increase in bacterial numbers, the activation of macrophages and neutrophils is markedly suppressed. In addition, Ft exerts a profound suppressive effect on the induction of pro-inflammatory cytokines by blocking signal transduction pathways. However, the Ft-encoded factors responsible for this immune subversion remain largely unidentified. No virulence-associated secretion systems, secreted proteins, or toxins have been identified for this category A pathogen. Our preliminary studies reveal that Ft possesses unique mechanisms for subversion of innate immunity. We have observed that antioxidants of Ft not only scavenge reactive oxygen and nitrogen species (ROS/RNS) generated in response to the infection, but also interfere with signaling pathways to suppress pro-inflammatory cytokines and macrophage activation. Based on these observations, we have developed a hypothesis that links robust oxidant-scavenging capacity of Ft to its ability to suppress macrophage function. The central hypothesis of this application is that "antioxidant defenses of Ft alter redox-sensitive signaling components to suppress macrophage microbicidal activity". This application is aimed at understanding the virulence mechanisms of Ft that creates an environment permissive for its intramacrophage survival, growth and virulence. We propose to test this hypothesis via the following specific aims: Aim 1. Investigate how antioxidants of Ft SchuS4 subvert macrophage microbicidal activity. Aim 2. Determine the redox-sensitive components that control NF-kB signaling and pro- inflammatory cytokine responses. Aim 3: Establish the mechanism of suppression of NOD-like receptor (NLR) mediated signaling and inhibition of microbicidal activity by Ft antioxidants. The proposed studies are relevant to public health, as the re-emergence of Ft as an agent of bioterrorism poses a serious public health threat. Knowledge of Francisella factors that both suppress immunity and contribute to pathogenesis may lead to tularemia therapies and safer, more effective vaccines.