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 这些研究解决了有关气道中的共生细菌如何预防肺炎细菌的知识差距。气道微生物组的下一代测序研究表明，特定的呼吸细菌与肺炎链球菌的抽象减少有关，肺炎链球菌是肺炎细菌的主要原因，表明可能受到潜在保护作用。这项工作的一个长期目标是通过优化“有益”气道核心介导的保护，以减少肺炎的燃烧。该项目将通过解决突出的呼吸道细菌如何影响肺肺炎链球菌的免疫清除率来推进这一目标。为此，我们开发了一种动物模型，该模型概括了在肺，prevotella prevotella selaninogenica中检测到的最丰富的细菌之一和肺炎链球菌感染的肺部感染之间的关系。初步数据表明，暴露于黑色素性疟原虫会动态改善肺肺炎链球菌的早期清除率。这种作用需要中性粒细胞，先天免疫接收器TLR2，以及包括TNFα在内的促炎细胞因子的产生。嗜中性粒细胞是从黑色素疟原虫大的小鼠的肺中纯化的，表达TLR2依赖性TNFα，在杀死肺炎链球菌方面更有效。此外，通过TLR2识别的黑色素生殖器脂蛋白的消化与保护和TNFα表达的丧失有关，突出了这些分子的关键作用。最后，通过抗炎细胞因子IL-10调节黑色素蛋白原诱导的感染，限制了TNFα相关的炎症反应，在24小时内对有效的肺炎链球菌清除非常重要。这些数据支持了黑色素蛋白原生成症的总体假设，即通过1）通过1）诱导以TLR2依赖性嗜中性粒细胞的激活为特征的先天免疫增强响应来预防肺炎链球菌感染，从而增强了肺链球菌的快速清除，而肺部的肺炎促成了2）支持IL-10依赖性的依赖性次要施加了IL-10依赖性的偶然性磨料。为了解决这一假设，AIM 1研究了增强肺炎链球菌杀伤所需的宿主因素，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。 AIM 2评估脂蛋白-TLR2信号如何与其他Prevotella配体相互作用相交，并通过与其他Prevotella物种进行比较来解决保护作用的概括性。在AIM 3中，将在IL-10或髓样细胞IL-10R缺乏的小鼠中评估肺细胞浸润，激活和病理学，以确定黑素激素诱导的，IL-10诱导的IL-10介导的感染和损伤的动力学和细胞靶标。这些研究共同提供了一种机械途径来研究微生物组肺轴，以指导开发新策略，以改善弱势群体中的气道共生介导的保护。