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：
10413242
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/10413242
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 antagonist 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

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.

线粒体应力形状宿主对细菌感染的反应项目摘要线粒体网络是代谢和感知细胞应激的中心枢纽，对塑造至关重要对感染的免疫反应。 Cardiolipin（Cl），一种在细菌中发现的阴离子磷脂和内部线粒体膜（IMM）将多蛋白呼吸链复合物锚定在膜，也可以部署到核定免疫超分子组织中心，例如炎症。在压力的条件下，例如感染，心磷脂被认为转移到线粒体外膜（OMM）或细胞外空间。控制CL的调节步骤细菌感染期间的易位，重塑和CL依赖性免疫反应很差理解。人类CL重塑酶的突变，tafazzin，导致X连锁的多链被称为巴特综合征的系统障碍，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，修改和信号传导能够对细菌的先天免疫反应的线粒体控制病原体。在这里，我们建议检验CL易位和修改调节的假设体内稳态和应力响应功能之间的切换，以推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，我们将扰动巨噬细胞CL在四个不同的步骤中：全球生物合成，OMM定位，氧化和重塑并定义在Cl依赖于Cl依赖的信号传导和效应器机制 MRSA感染。在这四个实验条件下，我们将定量跟踪CL膜使用超级分辨率显微镜在巨噬细胞中进行定位和细胞内运输。生化方法。最后，我们将研究对MRSA皮肤和柔软的先天免疫反应小鼠的组织感染在遗传上缺乏孔定位的CL或酶重塑的CL。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。这些研究将产生有关CL定位的机械洞察力并在先天免疫反应期间进行重塑，并有可能确定有效调节炎症。此外，这项工作将有助于将CL依赖性的上下文化在体内临床相关病原体框架内的先天免疫信号传导。