Mitochondrial stress shapes host responses to bacterial infection

线粒体应激塑造宿主对细菌感染的反应

基本信息

批准号：
10616749
负责人：
Mary O'Riordan
金额：
$ 40.57万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-27 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616749
关键词：
3-Methylglutaconic aciduria type 2 Affect Agonist Anabolism Animals Anti-Bacterial Agents Antibacterial Response Antioxidants Apoptosis Architecture Bacteria Bacterial Infections Biochemical Cardiolipins Cellular Stress Cellular biology Complex Coupled Development Disease Enzymes Exhibits Extracellular Space Functional disorder Generations Genetic Genetic Diseases Goals Homeostasis Host Defense Human Immune Immune response Immune signaling Immunity In Vitro Infection Infectious Skin Diseases Inflammasome Inflammation Injury Innate Immune Response Inner mitochondrial membrane Link Lipids Macrophage Membrane Metabolism Mitochondria Modeling Modification Mus Mutation Neutropenia Outcome Outer Mitochondrial Membrane Patients Peptides Phospholipids Positioning Attribute Predisposition Production Productivity Reactive Oxygen Species Recurrence Regulation Respiratory Chain Role Shapes Signal Transduction Skin Tissue Soft Tissue Infections Staphylococcus aureus infection Stress Surface System TLR4 gene Tail Testing Vesicle Work antagonist cardiolipin synthase cell injury clinically relevant confocal imaging cytokine defined contribution extracellular immune function immunoregulation in vivo insight methicillin resistant Staphylococcus aureus mouse model oxidation pathogen pathogenic bacteria pharmacologic respiratory respiratory protein response superresolution microscopy targeted treatment therapeutic target trafficking wound healing

项目摘要

Mitochondrial stress shapes host responses to bacterial infection Project Summary The mitochondrial network is a central hub for metabolism and sensing cellular stress, critical to shaping the immune response to infection. Cardiolipin (CL), an anionic phospholipid found in bacteria and in the inner mitochondrial membrane (IMM), anchors multi-protein respiratory chain complexes to the membrane and may also be deployed to nucleate immune supramolecular organizing centers such as the inflammasome. In conditions of stress, such as infection, cardiolipin is thought to translocate to the outer mitochondrial membrane (OMM) or the extracellular space. The regulatory steps that control CL translocation, remodeling and CL-dependent immune responses during bacterial infection are poorly understood. Mutations in the human CL remodeling enzyme, Tafazzin, result in an X-linked multi- system disorder known as Barth Syndrome, commonly associated with recurrent bacterial infections. The long-term goal of this proposal is to elucidate the mechanisms by which CL localization, modification and signaling enable mitochondrial control of the innate immune response to bacterial pathogens. Here we propose to test the hypothesis that CL translocation and modification regulates the switch between homeostatic and stress-responsive functions to drive innate immune responses to methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo. Specifically, we will perturb macrophage CL at four different steps: global biosynthesis, OMM-localization, oxidation and remodeling and define the signaling and effector mechanisms that are CL-dependent in the context of MRSA infection. Under these four experimental conditions, we will quantitatively track CL membrane localization and intracellular trafficking in macrophages using super resolution microscopy coupled with biochemical approaches. Finally, we will study the innate immune response to MRSA skin and soft tissue infection in mice genetically deficient in OMM-localized CL or enzymatically remodeled CL. We will also test the contribution of oxidized CL to in vivo antibacterial responses by treating MRSA-infected mice with a CL-targeted antioxidant. These studies will yield mechanistic insight into CL localization and remodeling during innate immune responses and potentially identify therapeutic targets for productively modulating inflammation. Additionally, this work will help contextualize CL-dependent innate immune signaling within the framework of a clinically relevant pathogen in vivo.

线粒体应激塑造宿主对细菌感染的反应项目概要线粒体网络是新陈代谢和感知细胞压力的中心枢纽，对于塑造细胞至关重要对感染的免疫反应。心磷脂 (CL)，一种存在于细菌和细菌中的阴离子磷脂线粒体内膜 (IMM)，将多蛋白呼吸链复合物锚定到膜，也可用于使免疫超分子组织中心成核，例如炎症小体。在压力条件下，例如感染，心磷脂被认为会转移到线粒体外膜（OMM）或细胞外空间。控制 CL 的监管步骤细菌感染期间的易位、重塑和 CL 依赖性免疫反应很差明白了。人类 CL 重塑酶 Tafazzin 的突变导致 X 连锁多称为巴斯综合症的系统疾病，通常与反复细菌感染有关。该提案的长期目标是阐明 CL 本地化的机制，修饰和信号传导使线粒体能够控制对细菌的先天免疫反应病原体。在这里，我们建议检验 CL 易位和修饰调节的假设稳态和应激反应功能之间的转换，以驱动先天免疫反应体外和体内耐甲氧西林金黄色葡萄球菌（MRSA）。具体来说，我们会扰乱巨噬细胞 CL 的四个不同步骤：整体生物合成、OMM 定位、氧化和重塑并定义 CL 依赖的信号传导和效应机制 MRSA 感染。在这四种实验条件下，我们将定量追踪CL膜使用超分辨率显微镜结合巨噬细胞的定位和细胞内运输生化方法。最后，我们将研究对 MRSA 皮肤和软组织的先天免疫反应。 OMM 局部 CL 或酶促重塑 CL 遗传缺陷小鼠的组织感染。我们还将通过治疗 MRSA 感染来测试氧化 CL 对体内抗菌反应的贡献具有 CL 靶向抗氧化剂的小鼠。这些研究将为 CL 定位提供机制上的见解和先天免疫反应过程中的重塑，并可能确定治疗靶点有效调节炎症。此外，这项工作将有助于将 CL 依赖的情境化体内临床相关病原体框架内的先天免疫信号传导。