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

• 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
• 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

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.

线粒体应激影响宿主对细菌感染的反应 项目摘要 线粒体网络是新陈代谢和感知细胞压力的中心枢纽，这对成型至关重要。 对感染的免疫反应。心磷脂(CL)，一种阴离子磷脂，存在于细菌和 内线粒体膜(IMM)将多蛋白呼吸链复合体锚定到 膜，也可以部署成核免疫超分子组织中心，如 发炎的人。在压力条件下，如感染，心磷脂被认为转移到 线粒体膜外(OMM)或细胞外间隙。控制CL的监管步骤 细菌感染时的移位、重塑和依赖CL的免疫反应很差 明白了。人类CL重塑酶Tafazzin的突变导致X-连锁多基因 被称为巴特综合征的系统障碍，通常与反复发生的细菌感染有关。 这项建议的长期目标是阐明CL本地化的机制， 修饰和信号传递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移位和修饰调节的假设 体内平衡和应激反应功能之间的切换，以驱动先天免疫反应 耐甲氧西林金黄色葡萄球菌(MRSA)的体内外研究。具体地说，我们将对 巨噬细胞CL的四个不同步骤：全球生物合成、OMM定位、氧化和 重塑并定义CL依赖的信号和效应器机制 MRSA感染。在这四种实验条件下，我们将对CL膜进行定量跟踪 巨噬细胞定位和细胞内转运的超分辨显微镜研究 生化方法。最后，我们将研究MRSA皮肤和软组织的先天免疫反应。 OMM定位CL或酶重塑CL基因缺陷小鼠的组织感染。我们 还将通过治疗MRSA感染来测试氧化的CL对体内抗菌反应的贡献 小鼠体内含有CL靶向抗氧化剂。这些研究将产生对CL本地化的机械性见解 在先天免疫反应中的作用和重构，并有可能确定治疗靶点 有效地调节炎症。此外，这项工作将有助于实现依赖CL的上下文 体内临床相关病原体框架内的先天免疫信号。