Airway Prevotella enhance innate immune-mediated protection against lung infection
气道普雷沃氏菌增强先天免疫介导的肺部感染保护
基本信息
- 批准号:10561450
- 负责人:
- 金额:$ 49.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-20 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AddressAlveolar MacrophagesAnimal ModelAnti-Inflammatory AgentsAntibiotic TherapyBacteriaBacterial PneumoniaCellsCellular InfiltrationClinicalDataDevelopmentDigestionExposure toGoalsHourHumanImmuneImmunologic ReceptorsImmunotherapeutic agentImmunotherapyIndividualInfectionInflammationInflammatoryInflammatory ResponseInjuryInnate Immune ResponseIntegration Host FactorsInterleukin-10InterventionInvadedKineticsKnowledgeLigandsLipopolysaccharidesLipoproteinsLungLung infectionsMediatingMolecularMusMyeloid Cell ActivationMyeloid CellsNeutrophil ActivationNeutrophil InfiltrationOutcomePathologyPathway interactionsPersonsPhenotypePneumococcal PneumoniaPneumoniaPredispositionPrevotellaPrevotella melaninogenicaProbioticsProductionPulmonary PathologyRegulationResolutionRespiratory DiseaseRoleSignal TransductionSourceStreptococcus pneumoniaeTLR2 geneTLR4 geneTNF geneTNFRSF1A geneTranslationsVulnerable PopulationsWorkantagonistcellular targetingclinically relevantco-infectioncommensal bacteriacommunity acquired pneumoniacytokinedefined contributiondesignhost microbiomeimprovedinfection risklung healthlung microbiomemembermicrobialmicrobiotamouse modelneutrophilnext generation sequencingnovelopportunistic pathogenoverexpressionpreventprotective effectreceptorrecruitrespiratoryrespiratory microbiomerestraintsingle-cell RNA sequencingsynergism
项目摘要
Project Summary
These studies address the large gap in knowledge regarding how commensal bacteria in the airway protect against bacterial pneumonia. Next generation sequencing studies of the airway microbiome have revealed that specific respiratory bacteria are associated with a reduced abundance of Streptococcus pneumoniae, a major cause of bacterial pneumonia, indicating a potentially protective role. A long-term goal of this work is to reduce the burden of pneumonia by optimizing protection mediated by `beneficial' airway commensals. This project will advance this goal by addressing how a prominent respiratory bacterium influences immune-mediated clearance of S. pneumoniae from the lung. For this purpose, we developed an animal model that recapitulates the relationship between one of the most abundant bacteria detected in the lung, Prevotella melaninogenica, and lung infection with S. pneumoniae. Preliminary data indicate that exposure to P. melaninogenica dramatically improves early clearance of S. pneumoniae from the lung. This effect requires neutrophils, the innate immune receptor TLR2, and the production of pro-inflammatory cytokines, including TNFα. Neutrophils purified from the lungs of P. melaninogenica-exposed mice express TLR2-dependent TNFα and are more effective at killing S. pneumoniae. Further, digestion of P. melaninogenica lipoproteins, which are recognized by TLR2, is associated with loss of protection and TNFα expression, highlighting key roles for these molecules. Finally, regulation of P. melaninogenica-induced inflammation by the anti-inflammatory cytokine IL-10 restrains the TNFα-associated inflammatory response within 24 hours and is important for effective S. pneumoniae clearance. These data support the overall hypothesis that P. melaninogenica serves complementary roles to protect against S. pneumoniae infection by 1) inducing an innate immune response characterized by TLR2-dependent activation of neutrophils, which enhances rapid clearance of S. pneumoniae from the lung, while 2) supporting IL-10 dependent abrogation of infection-associated inflammatory damage. To address this hypothesis, Aim 1 investigates host factors required for enhanced S. pneumoniae killing, including alveolar macrophages, neutrophil TNFα signaling, and baseline immune priming by the endogenous microbiota. Aim 2 evaluates how lipoprotein-TLR2 signaling intersects with other Prevotella ligand-TLR interactions and addresses the generalizability of the protective effect by comparison with other Prevotella species. In Aim 3, lung cellular infiltration, activation and pathology will be assessed over the course of S. pneumoniae co-infection in mice with deficiencies in IL-10 or myeloid cell IL-10R to determine the kinetics and cellular targets of P. melaninogenica-induced, IL-10-mediated control of inflammation and injury. Together, these studies provide a mechanistic pathway to investigate the microbiome-lung axis in order to guide the development of new strategies to improve airway commensal-mediated protection in vulnerable populations.
项目摘要
这些研究解决了关于呼吸道共生细菌如何预防细菌性肺炎的巨大知识缺口。对呼吸道微生物组的下一代测序研究表明,特定的呼吸道细菌与肺炎链球菌丰度降低有关,肺炎链球菌是细菌性肺炎的主要原因,表明可能起到保护作用。这项工作的一个长期目标是通过优化由“有益的”呼吸道共生体介导的保护来减轻肺炎的负担。这个项目将通过解决一种突出的呼吸道细菌如何影响免疫介导的肺炎链球菌从肺中的清除来推进这一目标。为此,我们开发了一种动物模型,它概括了在肺部检测到的最丰富的细菌之一--普雷沃特氏黑素生成菌--与肺炎链球菌肺部感染之间的关系。初步数据表明,暴露于产黑素假单胞菌可显著改善肺炎链球菌从肺中的早期清除。这种作用需要中性粒细胞,先天免疫受体TLR2,以及包括肿瘤坏死因子α在内的促炎细胞因子的产生。从暴露于黑素假单胞菌的小鼠肺中提纯的中性粒细胞表达TLR2依赖的肿瘤坏死因子α,并且更有效地杀灭肺炎链球菌。此外,TLR2识别的产黑素假单胞菌脂蛋白的消化与保护作用的丧失和肿瘤坏死因子α的表达有关,从而突出了这些分子的关键作用。最后,抗炎细胞因子IL-10调节产黑素假单胞菌引起的炎症反应,在24小时内抑制肿瘤坏死因子α相关的炎症反应,对有效清除肺炎链球菌很重要。这些数据支持这样一种总体假设,即产黑素假单胞菌通过1)诱导以TLR2依赖的中性粒细胞激活为特征的先天免疫反应,从而增强肺炎链球菌从肺中的快速清除,从而发挥互补作用来预防肺炎链球菌感染;2)支持IL-10依赖的消除感染相关的炎症损伤。为了解决这一假设,Aim 1研究了增强肺炎链球菌杀灭所需的宿主因素,包括肺泡巨噬细胞、中性粒细胞肿瘤坏死因子α信号和内源性微生物群的基线免疫启动。目的2评价脂蛋白-TLR2信号与普氏杆菌配体-TLR相互作用的相互作用,并通过与其他普氏杆菌物种的比较,说明这种保护作用的普遍性。在目标3中,将在IL-10或髓系细胞IL-10R缺乏的小鼠中评估肺炎链球菌混合感染过程中的肺细胞渗透、激活和病理,以确定产黑素假单胞菌诱导的IL-10介导的炎症和损伤控制的动力学和细胞靶点。总之,这些研究提供了一种机制途径来研究微生物-肺轴,以指导新策略的发展,以改善脆弱人群的呼吸道共生介导的保护。
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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Sarah E Clark其他文献
Combined Epigenetic Therapy to Induce Latency II/III Antigen Expression in Latency I EBVsup+/sup Lymphoma
联合表观遗传疗法诱导潜伏 I 型 EB 病毒阳性淋巴瘤中的潜伏 II/III 抗原表达
- DOI:
10.1182/blood-2024-201570 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Isabella Y Kong;Sarah E Clark;Suhong Sun;Vicenta Trujillo-Alonso;Alicia Alonso;Roberta Zappasodi;Ethel Cesarman;Lisa Giulino Roth - 通讯作者:
Lisa Giulino Roth
Combined Epigenetic Therapy to Induce Latency II/III Antigen Expression in Latency I EBV<sup>+</sup> Lymphoma
- DOI:
10.1182/blood-2024-201570 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Isabella Y Kong;Sarah E Clark;Suhong Sun;Vicenta Trujillo-Alonso;Alicia Alonso;Roberta Zappasodi;Ethel Cesarman;Lisa Giulino Roth - 通讯作者:
Lisa Giulino Roth
Contextual assessment of the breadth and level of investments made by prevention initiatives to improve nutrition and prevent obesity in Los Angeles County, 2010–2015
对 2010-2015 年洛杉矶县改善营养和预防肥胖的预防举措的投资广度和水平的背景评估
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:2.8
- 作者:
Katherine Sutton;Sarah E Clark;Jack Thompson;Lisa Craypo;Liz Schwarte;T. Kuo - 通讯作者:
T. Kuo
Insights into the role of the respiratory tract microbiome in defense against bacterial pneumonia
对呼吸道微生物组在抵御细菌性肺炎中作用的深入洞察
- DOI:
10.1016/j.mib.2024.102428 - 发表时间:
2024-02-01 - 期刊:
- 影响因子:7.500
- 作者:
Zoe G Drigot;Sarah E Clark - 通讯作者:
Sarah E Clark
Sarah E Clark的其他文献
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{{ truncateString('Sarah E Clark', 18)}}的其他基金
Host factors influencing early clearance of Streptococcus pneumoniae from the middle ear following invasion from the nasopharynx
影响肺炎链球菌从鼻咽部侵入后中耳早期清除的宿主因素
- 批准号:
10551220 - 财政年份:2022
- 资助金额:
$ 49.17万 - 项目类别:
Host factors influencing early clearance of Streptococcus pneumoniae from the middle ear following invasion from the nasopharynx
影响肺炎链球菌从鼻咽部侵入后中耳早期清除的宿主因素
- 批准号:
10358434 - 财政年份:2022
- 资助金额:
$ 49.17万 - 项目类别:
Natural killer cell-derived IL-10 and immunity to Listeria
自然杀伤细胞衍生的 IL-10 和对李斯特菌的免疫力
- 批准号:
8975083 - 财政年份:2014
- 资助金额:
$ 49.17万 - 项目类别:
Natural killer cell-derived IL-10 and immunity to Listeria
自然杀伤细胞衍生的 IL-10 和对李斯特菌的免疫力
- 批准号:
8783266 - 财政年份:2014
- 资助金额:
$ 49.17万 - 项目类别:
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