Innate Immune Response to S. aureus Biofilm
对金黄色葡萄球菌生物膜的先天免疫反应
基本信息
- 批准号:10665032
- 负责人:
- 金额:$ 58.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAnabolismAnti-Bacterial AgentsAnti-Inflammatory AgentsAntibioticsCellsCellular Metabolic ProcessChIP-seqDataDevelopmentDiseaseEnvironmentExcisionFundingGenus staphylococcusGlycolysisGoalsHDAC4 geneHip region structureHistone Deacetylase InhibitorHistonesImmuneImmune responseImpairmentImplantIncidenceInfectionInfiltrationInflammatoryInnate Immune ResponseInterleukin-10Knockout MiceLaboratoriesLeukocytesLibrariesMacrophageMetabolicMetabolic PathwayMetabolismMicrobial BiofilmsModelingMolecularMolecular Mechanisms of ActionMusMyeloid-derived suppressor cellsNebraskaNeutrophil InfiltrationOligomycinsOxidative PhosphorylationPathway interactionsPatientsPeriprosthetic joint infectionPhenotypeProductionPropertyProsthesisRoleSourceStaphylococcus aureusTranslatingUrokinaseWorkaerobic glycolysisgenome-wideimprovedin vivoinhibitorinnovationknee replacement arthroplastymetabolomemetabolomicsmonocytemutantnanoparticleneutrophilprogramspromoterrecruit
项目摘要
Staphylococcus aureus (S. aureus) is a leading cause of biofilm-associated prosthetic joint infections (PJIs)
typified by an anti-inflammatory cellular milieu. The inflammatory phenotype of leukocytes is intimately tied to
their metabolic status, where anti-inflammatory MΦs primarily rely on oxidative phosphorylation (OxPhos) and
pro-inflammatory MΦs utilize glycolysis. Monocytes are also polarized toward an anti-inflammatory state during
S. aureus PJI, which our preliminary data shows coincides with an OxPhos bias. We have devised an innovative
approach to metabolically re-reprogram biofilm-associated monocytes to promote glycolysis using cell-targeted
nanoparticles containing the OxPhos inhibitor oligomycin. Treatment of established biofilms with oligomycin
nanoparticles promoted monocyte pro-inflammatory activity concomitant with increased neutrophil recruitment,
leading to biofilm clearance. During the recent PPG cycle, our laboratory was the first to identify that myeloid-
derived suppressor cells (MDSCs) skew biofilm-associated monocytes toward an anti-inflammatory state, in part,
through IL-10 production. Therefore, we screened the Nebraska Transposon Mutant Library to identify mutants
impaired in their ability to trigger IL-10 production. Significant hits involved in lactate biosynthesis were identified,
and our preliminary data support a role for S. aureus-derived lactate in organizing the anti-inflammatory biofilm
milieu, progressing from MDSCs/monocytes as a target to defining the molecular mechanism of action. First,
during PJI, D- and L-lactate levels are reduced in S. aureus ddh1 and ldh1/ldh2 mutants, respectively,
concomitant with significant reductions in MDSC infiltrates and IL-10 production, which translates into enhanced
leukocyte recruitment, and biofilm clearance. Second, the IL-10 promoter is activated by acetylation and our
ChIP-Seq data demonstrate that histone promoter acetylation is dramatically increased genome-wide in
leukocytes recovered from WT vs. ldh1/ldh2 infected mice, providing molecular evidence that S. aureus biofilm-
derived lactate functions as a histone deacetylase inhibitor (HDACi). Our central P01 hypothesis is that S.
aureus biofilm development creates unique metabolic niches that promote an immune suppressive
environment. In Project 4, we will explore the existence of a metabolic triad between S. aureus biofilm, MDSCs,
and monocytes, whereby biofilm-derived lactate promotes leukocyte anti-inflammatory properties, in part, via IL-
10 production, contributing to biofilm persistence. This metabolic crosstalk and the molecular mechanisms
responsible for this interplay will be explored in the following Specific Aims. 1) Establish that leukocyte
metabolism can be targeted in vivo to promote pro-inflammatory activity and biofilm clearance; 2) Investigate the
role of S. aureus biofilm-derived lactate in promoting MDSC and monocyte anti-inflammatory activity by
stimulating IL-10 production; and 3) Determine whether S. aureus biofilm-derived lactate regulates IL-10
production by inhibiting histone deacetylase (HDAC) activity. These studies will inform our long-term goal of
targeting metabolic pathways that disarm anti-bacterial innate immune defenses to facilitate biofilm eradication.
金黄色葡萄球菌(S.金黄色葡萄球菌)是生物膜相关人工关节感染(PJIs)的主要原因
其特征在于抗炎细胞环境。白细胞的炎性表型与白细胞分化密切相关。
其代谢状态,其中抗炎MΦ主要依赖氧化磷酸化(OxPhos)和
促炎性MΦ利用糖酵解。单核细胞也被极化至抗炎状态
S.金黄色葡萄球菌PJI,我们的初步数据显示与OxPhos偏倚一致。我们设计了一种创新的
利用细胞靶向技术对生物膜相关单核细胞进行代谢重编程以促进糖酵解方法
含有OxPhos抑制剂寡霉素的纳米颗粒。用寡霉素处理已形成的生物膜
纳米颗粒促进单核细胞促炎活性,同时增加嗜中性白细胞募集,
从而导致生物膜的清除。在最近的PPG周期中,我们的实验室是第一个发现髓系-
衍生的抑制细胞(MDSCs)使生物膜相关的单核细胞偏向抗炎状态,部分,
通过IL-10的产生。因此,我们筛选了内布拉斯加州转座子突变体文库,以鉴定突变体
其触发IL-10产生的能力受损。鉴定了涉及乳酸盐生物合成的显著命中,
初步数据支持S的作用。金黄色葡萄球菌衍生的乳酸盐在组织抗炎生物膜中的作用
从MDSCs/单核细胞作为靶点发展到定义分子作用机制。第一、
在PJI期间,S.金黄色葡萄球菌ddh 1和ldh 1/ldh 2突变体,
伴随着MDSC浸润和IL-10产生的显著减少,这转化为MDSC浸润和IL-10产生的增强
白细胞募集和生物膜清除。第二,IL-10启动子通过乙酰化激活,而我们的研究发现,IL-10启动子在IL-10的表达上调。
ChIP-Seq数据表明,在正常人中,组蛋白启动子乙酰化在全基因组范围内显著增加。
从WT和ldh 1/ldh 2感染小鼠中回收的白细胞,提供了S.金黄色葡萄球菌生物膜
衍生的乳酸盐起组蛋白脱乙酰酶抑制剂(HDACi)的作用。我们的中心P01假设是S.
金黄色葡萄球菌生物膜的形成创造了独特的代谢生态位,促进免疫抑制
环境在项目4中,我们将探讨S.金黄色葡萄球菌生物膜、MDSCs
和单核细胞,由此生物膜衍生的乳酸盐促进白细胞抗炎特性,部分是通过IL-
10的产量,有助于生物膜的持续。这种代谢串扰及其分子机制
将在以下具体目标中探讨造成这种相互作用的原因。1)确定白细胞
代谢可在体内靶向促进促炎活性和生物膜清除; 2)研究
S.金黄色葡萄球菌生物膜衍生乳酸盐促进MDSC和单核细胞抗炎活性
刺激IL-10的产生;和3)确定S.金黄色葡萄球菌生物膜衍生乳酸盐调节IL-10
通过抑制组蛋白脱乙酰基酶(HDAC)活性而产生。这些研究将为我们的长期目标提供信息
靶向解除抗细菌先天免疫防御的代谢途径以促进生物膜根除。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Tammy L Kielian其他文献
Tammy L Kielian的其他文献
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{{ truncateString('Tammy L Kielian', 18)}}的其他基金
Modulating granulocytic myeloid-derived suppressor cell (G-MDSC) metabolic activity to promote Staphylococcus aureus biofilm clearance
调节粒细胞骨髓源性抑制细胞 (G-MDSC) 代谢活性以促进金黄色葡萄球菌生物膜清除
- 批准号:
10738662 - 财政年份:2023
- 资助金额:
$ 58.82万 - 项目类别:
T cell-innate immune crosstalk regulates Staphylococcus aureus craniotomy infection
T细胞先天免疫串扰调节金黄色葡萄球菌开颅感染
- 批准号:
10590634 - 财政年份:2022
- 资助金额:
$ 58.82万 - 项目类别:
Immune mechanisms that promote S. aureus persistence during craniotomy-associated biofilm infection
开颅手术相关生物膜感染期间促进金黄色葡萄球菌持续存在的免疫机制
- 批准号:
9896877 - 财政年份:2018
- 资助金额:
$ 58.82万 - 项目类别:
Immune mechanisms that promote S. aureus persistence during craniotomy-associated biofilm infection
开颅手术相关生物膜感染期间促进金黄色葡萄球菌持续存在的免疫机制
- 批准号:
10375439 - 财政年份:2018
- 资助金额:
$ 58.82万 - 项目类别:
Therapeutic targeting of aberrant glial function during Juvenile Batten Disease
幼年巴顿病期间异常神经胶质功能的治疗靶向
- 批准号:
8788453 - 财政年份:2014
- 资助金额:
$ 58.82万 - 项目类别:
Therapeutic targeting of aberrant glial function during Juvenile Batten Disease
幼年巴顿病期间异常神经胶质功能的治疗靶向
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8660113 - 财政年份:2014
- 资助金额:
$ 58.82万 - 项目类别:
Contribution of extracellular enzymes to Staphylococcus aureus biofilm development
胞外酶对金黄色葡萄球菌生物膜发育的贡献
- 批准号:
10665029 - 财政年份:2009
- 资助金额:
$ 58.82万 - 项目类别:
The Role of Nuclease in Biofilm Development and Disease
核酸酶在生物膜发育和疾病中的作用
- 批准号:
7750239 - 财政年份:2009
- 资助金额:
$ 58.82万 - 项目类别:
Contribution of extracellular enzymes to Staphylococcus aureus biofilm development
胞外酶对金黄色葡萄球菌生物膜发育的贡献
- 批准号:
10461797 - 财政年份:2009
- 资助金额:
$ 58.82万 - 项目类别:
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