Redox stress responses in Clostridium difficile: mechanisms and implications

 描述（由申请方提供）：本提案的总体目标是询问肠道病原体艰难梭菌的胃肠道（GI）生态位建立。我们已经确定了一种独特的氧解毒酶，超氧化物还原酶（SOR），它促进C。在胃肠道中难以存活。这项工作的直接影响将是validae SOR和其他氧化还原蛋白作为新的干预目标，旨在防止C。艰难的殖民提出了三个具体目标。在目标1中，我们将描述氧和活性氧（ROS）暴露对C。胃肠道中的艰难定位和存活。在目标2中，我们将评估宿主ROS缺乏对C.艰难的生态位建立。在目标3中，我们将全面绘制C。difficile氧化还原应激反应纲要。所有拟议的研究将使用最近的临床分离的C。困难重重 通过正在进行的疾病监测研究获得。对于目的1和2，将采用两种动物模型，并使用我们专门为这些研究开发的新型定殖示踪剂通过活体动物和离体成像跟踪细菌建立。对于目标3，我们将采用下一代氧化还原蛋白质组学（ROSics）方法。

 DESCRIPTION (provided by applicant): The overall goal of this proposal is interrogate gastrointestinal (GI) niche establishment of the diarrheagenic pathogen, Clostridium difficile. We have identified a unique oxygen detoxifying enzyme, superoxide reductase (SOR), which promotes C. difficile survival in the GI tract. The immediate impact of this work will be to validae SOR and other redox proteins as novel targets for interventions designed to prevent C. difficile colonization. Three Specific Aims are proposed. In Aim 1, we will delineate the impact of oxygen and reactive oxygen species (ROS) exposure on C. difficile localization and survival in the GI tract. In Aim 2, we will assess the impact of host ROS deficiency on C. difficile niche establishment. In Aim 3, we will comprehensively map the C. difficile redox-stress response compendium. All the proposed studies will use recent clinical isolates of C. difficile that we have obtained through ongoing disease surveillance studies. For Aims 1 and 2, two animal models will be employed, and bacterial establishment tracked via live-animal and ex vivo imaging using a novel colonization tracer we have specifically developed for these studies. For Aim 3, we will employ next-generation redox proteomics (ROSics) approaches.