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.

项目总结