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

• 批准号: 10561450
• 负责人: Sarah E Clark
• 金额: $ 49.17万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10561450
• 关键词: Address; Alveolar Macrophages; Animal Model; Anti-Inflammatory Agents; Antibiotic Therapy; Bacteria; Bacterial Pneumonia; Cells; Cellular Infiltration; Clinical; Data; Development; Digestion; Exposure to; Goals; Hour; Human; Immune; Immunologic Receptors; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Integration Host Factors; Interleukin-10; Intervention; Invaded; Kinetics; Knowledge; Ligands; Lipopolysaccharides; Lipoproteins; Lung; Lung infections; Mediating; Molecular; Mus; Myeloid Cell Activation; Myeloid Cells; Neutrophil Activation; Neutrophil Infiltration; Outcome; Pathology; Pathway interactions; Persons; Phenotype; Pneumococcal Pneumonia; Pneumonia; Predisposition; Prevotella; Prevotella melaninogenica; Probiotics; Production; Pulmonary Pathology; Regulation; Resolution; Respiratory Disease; Role; Signal Transduction; Source; Streptococcus pneumoniae; TLR2 gene; TLR4 gene; TNF gene; TNFRSF1A gene; Translations; Vulnerable Populations; Work; antagonist; cellular targeting; clinically relevant; co-infection; commensal bacteria; community acquired pneumonia; cytokine; defined contribution; design; host microbiome; improved; infection risk; lung health; lung microbiome; member; microbial; microbiota; mouse model; neutrophil; next generation sequencing; novel; opportunistic pathogen; overexpression; prevent; protective effect; receptor; recruit; respiratory; respiratory microbiome; restraint; single-cell RNA sequencing; synergism

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中的细菌如何预防细菌性肺炎的知识的巨大空白。对气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（细菌性肺炎的主要原因）丰度降低有关，这表明了潜在的保护作用。这项工作的一个长期目标是通过优化“有益的”气道呼吸系统介导的保护来减轻肺炎的负担。这个项目将通过解决一个突出的呼吸道细菌如何影响免疫介导的S。肺炎从肺部。为此，我们开发了一种动物模型，该模型概括了肺中检测到的最丰富的细菌之一，产黑色素普雷沃氏菌和肺感染S。肺炎。初步数据表明，暴露于P. melaninogenica显着提高早期清除S。肺炎从肺部。这种作用需要中性粒细胞、先天免疫受体TLR 2和促炎细胞因子（包括TNFα）的产生。从暴露于黑色素原杆菌的小鼠的肺中纯化的中性粒细胞表达TLR 2依赖性TNFα，并且在杀死S.肺炎。此外，由TLR 2识别的黑色素原卟啉单胞菌脂蛋白的消化与保护和TNFα表达的丧失相关，突出了这些分子的关键作用。最后，通过抗炎细胞因子IL-10调节黑色素原卟啉单胞菌诱导的炎症，在24小时内抑制了TNFα相关的炎症反应，这对有效的S.肺炎清除率。这些数据支持了黑色素原杆菌在抵抗沙门氏菌中起补充作用的总体假设。肺炎链球菌感染通过1）诱导以嗜中性粒细胞的TLR 2依赖性活化为特征的先天性免疫应答，其增强对肺炎链球菌的快速清除。2）支持IL-10依赖性消除感染相关的炎性损伤。为了解决这一假设，目的1调查宿主因素所需的增强S。pneumoniae杀伤，包括肺泡巨噬细胞、中性粒细胞TNFα信号传导和内源性微生物群的基线免疫启动。目的2评估脂蛋白-TLR 2信号传导如何与其他普雷沃氏菌配体-TLR相互作用交叉，并通过与其他普雷沃氏菌属物种的比较来解决保护作用的普遍性。在目标3中，将在S.本发明的目的是在具有IL-10或髓样细胞IL-10 R缺陷的小鼠中检测肺炎链球菌共感染的细胞因子，以确定黑色素原卟啉单胞菌诱导的IL-10介导的炎症和损伤控制的动力学和细胞靶标。总之，这些研究提供了一种机制途径来研究微生物组-肺轴，以指导新策略的开发，从而改善易感人群中气道炎症介导的保护作用。