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:
- 金额:$ 40.57万
- 依托单位:
- 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:
- 关键词:3-Methylglutaconic aciduria type 2AffectAgonistAnabolismAnimalsAnti-Bacterial AgentsAntibacterial ResponseAntioxidantsApoptosisArchitectureBacteriaBacterial InfectionsBiochemicalCardiolipinsCellular StressCellular biologyComplexCoupledDevelopmentDiseaseEnzymesExhibitsExtracellular SpaceFunctional disorderGenerationsGeneticGenetic DiseasesGoalsHomeostasisHost DefenseHumanImmuneImmune responseImmune signalingImmunityIn VitroInfectionInfectious Skin DiseasesInflammasomeInflammationInjuryInnate Immune ResponseInner mitochondrial membraneLightLinkLipidsMembraneMetabolismMicroscopyMitochondriaModelingModificationMusMutationNeutropeniaOutcomeOuter Mitochondrial MembraneOxidesPatientsPeptidesPharmacologyPhospholipidsPositioning AttributeProductionReactive Oxygen SpeciesRecurrenceRegulationResolutionRespiratory ChainRoleShapesSignal TransductionSkin TissueSoft Tissue InfectionsStaphylococcus aureus infectionStressSurfaceSystemTLR4 geneTailTestingVesicleWorkantagonistcardiolipin synthasecell injuryclinically relevantconfocal imagingcytokinedefined contributionextracellularimmune functionin vivoinsightmacrophagemethicillin resistant Staphylococcus aureusmouse modeloxidationpathogenpathogenic bacteriarespiratoryresponsetargeted treatmenttherapeutic targettraffickingwound 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mary O'Riordan其他文献
Mary O'Riordan的其他文献
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{{ truncateString('Mary O'Riordan', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 40.57万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 40.57万 - 项目类别:
Mechanisms of host defense against membrane damage by pore-forming toxins
宿主防御成孔毒素膜损伤的机制
- 批准号:
8699346 - 财政年份:2013
- 资助金额:
$ 40.57万 - 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
- 批准号:
8389503 - 财政年份:2012
- 资助金额:
$ 40.57万 - 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
- 批准号:
8485542 - 财政年份:2012
- 资助金额:
$ 40.57万 - 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
- 批准号:
8854184 - 财政年份:2012
- 资助金额:
$ 40.57万 - 项目类别:
Mobilization of lysosome anti-microbial defenses by the unfolded protein response
通过未折叠的蛋白质反应动员溶酶体抗微生物防御
- 批准号:
8364443 - 财政年份:2012
- 资助金额:
$ 40.57万 - 项目类别:
Mobilization of lysosome anti-microbial defenses by the unfolded protein response
通过未折叠的蛋白质反应动员溶酶体抗微生物防御
- 批准号:
8519298 - 财政年份:2012
- 资助金额:
$ 40.57万 - 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
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8891354 - 财政年份:2012
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