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: 10317161
• 负责人: Mary O'Riordan
• 金额: $ 41.48万
• 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/10317161
• 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; Light; Link; Lipids; Membrane; Metabolism; Microscopy; Mitochondria; Modeling; Modification; Mus; Mutation; Neutropenia; Outcome; Outer Mitochondrial Membrane; Oxides; Patients; Peptides; Pharmacology; Phospholipids; Positioning Attribute; Production; Reactive Oxygen Species; Recurrence; Regulation; Resolution; Respiratory Chain; Role; Shapes; Signal Transduction; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus infection; Stress; Surface; System; TLR4 gene; Tail; Testing; Vesicle; Work; cardiolipin synthase; cell injury; clinically relevant; confocal imaging; cytokine; defined contribution; extracellular; immune function; in vivo; insight; macrophage; methicillin resistant Staphylococcus aureus; mouse model; oxidation; pathogen; pathogenic bacteria; respiratory; response; 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应激的中心枢纽，对塑造 对感染的免疫反应心磷脂（CL）是一种在细菌和大肠杆菌中发现的阴离子磷脂。 线粒体内膜（IMM）将多蛋白质呼吸链复合物锚定在线粒体膜上。 膜，并且还可以部署成核免疫超分子组织中心， 炎性小体在压力条件下，如感染，心磷脂被认为是易位到 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依赖性免疫应答较差， 明白人类CL重塑酶Tafazzin的突变导致X连锁多基因突变。 系统紊乱，称为巴斯综合征，通常与复发性细菌感染有关。 该提案的长期目标是阐明CL定位的机制， 修饰和信号传导使线粒体能够控制对细菌的先天免疫应答， 病原体在这里，我们提出测试的假设，CL易位和修改调节 体内平衡和应激反应功能之间的转换，以驱动先天免疫反应， 耐甲氧西林金黄色葡萄球菌（MRSA）在体外和体内。具体地说，我们将扰动 巨噬细胞CL在四个不同的步骤：全球生物合成，OMM定位，氧化和 重塑和定义的信号和效应机制，是CL依赖的背景下， MRSA感染。在这四个实验条件下，我们将定量跟踪CL膜， 巨噬细胞的定位和细胞内运输，使用超分辨率显微镜结合 生物化学方法。最后，我们将研究对MRSA皮肤和软组织的先天免疫反应。 OMM定位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感染的小鼠来测试氧化CL对体内抗菌反应的贡献。 用CL靶向抗氧化剂治疗小鼠。这些研究将产生机制的洞察CL本地化 和重塑，并可能确定治疗靶点， 有效地调节炎症。此外，这项工作将有助于将依赖CL的背景化 在体内临床相关病原体的框架内的先天免疫信号传导。