Defenses against Acute Chronic Infection with C pneumoniae

防御肺炎衣原体急性慢性感染

• 批准号: 7790031
• 负责人: Robin R Ingalls
• 金额: $ 25.76万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790031
• 关键词: Acute; Acute Pneumonia; Acute respiratory infection; Adhesions; Alveolar Macrophages; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Back; Bacteria; Bacterial Pneumonia; Blood; Blood Platelets; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Bronchitis; Cardiovascular Diseases; Cathepsins B; Cells; Characteristics; Chlamydia; Chlamydophila pneumoniae; Chronic; Collaborations; Complex; Confocal Microscopy; Cytokine Signaling; Cytoplasmic Granules; Cytosol; Data; Data Analyses; Development; Disease; Endothelial Cells; Equilibrium; Feedback; Foam Cells; Framingham Heart Study; Genes; Genetic; Goals; Host Defense; Human; Image; Immune; Immune response; Immunologic Receptors; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Interleukins; Invaded; Knock-in Mouse; Knockout Mice; Lead; Leishmania; Lesion; Life; Ligands; Link; Lipopolysaccharides; Listeria; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Membrane; Modeling; Molecular; Monitor; Morbidity - disease rate; Mouse Strains; Mus; Mycobacterium tuberculosis; Natural Immunity; Normal tissue morphology; Organism; Outcome; Pathogenesis; Pathway interactions; Personal Communication; Pharyngitis; Platelet Activation; Platelet aggregation; Play; Pneumonia; Porphyromonas gingivalis; Prevention; Process; Program Research Project Grants; Radio; Recruitment Activity; Relative (related person); Resistance; Resolution; Role; Secondary to; Signal Pathway; Signal Transduction; Sinusitis; Symptoms; TLR2 gene; Testing; Time; Up-Regulation; Vascular Endothelial Cell; aortic arch; atypical pneumonia; autocrine; base; cell type; cohort; cytokine; human disease; in vivo; innovation; macrophage; microorganism; mortality; mouse model; novel; novel strategies; offspring; pathogen; promoter; research study; respiratory; response

The ability of a host to sense invasion by pathogenic organisms and respond appropriately to control infection is paramount to survival. In some cases, however, an exaggerated inflammatory response can lead to bystander injury and systemic inflammatory symptoms, possibly contributing to the morbidity and mortality associated with overwhelming infections. The pro-inflammatory cytokine interleukin (IL)-1 is a critical mediator of host defense against a variety of infectious states. For example, IL-1 is produced in the lung after intratracheal administration of lipopolysaccharide, and its presence is directly associated with lung inflammation and bacterial burden in pneumonia. IL-1 is required for control of a variety of intracellular pathogens, such as Listeria, Leishmania, and Mycobacterium tuberculosis. However, little is known about the role of IL-1 in control of Chlamydophila pneumoniae, an obligate intracellular bacteria that is associated with a variety of acute infectious processes, sush as atypical pneumonia, bronchitis, and pharyngitis; chronic infection with C. pneumoniae has also been linked to a variety of chronic inflammatory states, including atherosclerosis. The central hypothesis of this proposal is that C. pneumoniae-induced IL-1 fiplays contradictory roles in the defense of acute vs. chronic infections. Our preliminary data demonstrates that C. pneumoniae, unlike other related chlamydia species, has the unique ability to directly induce IL-1 ft secretion from murine bone marrow derived macrophages, and that this induction is dependent on the NALP3/ASC inflammasome complex. We believe that while IL-1 (3 plays an important role in resolution of acute pneumonia, its induction in the setting of chronic infection contributes to the inflammation that is characteristic of atherosclerotic plaque formation. To further understand the role of C. pnet/mon/ae-induced IL-ip in the development of disease, we propose the following Specific Aims: (1) To define the molecular mechanism behind the induction of IL-1 p by macrophages infected with C. pneumoniae; (2) To examine the role IL-ip and the IL-1 receptor in acute bacterial pneumonia and the systemic inflammatory response; and (3) To examine the role IL-ip and the IL-1 receptor in the chronic inflammatory plaque formation that is characteristic of atherosclerosis.

宿主通过病原生物感知入侵并适当反应控制的能力 感染对于生存至关重要。但是，在某些情况下，夸张的炎症反应会导致旁观者损伤和全身性炎症症状，可能导致与压倒性感染相关的发病率和死亡率。促炎性细胞因子白介素（IL）-1是针对各种传染性状态的宿主防御的关键介体。例如，在气管内给药脂多糖后，在肺中产生IL-1，其存在与肺炎的肺部炎症和细菌负担直接相关。 IL-1是控制多种细胞内病原体（例如李斯特菌，利什曼原虫和结核分枝杆菌）所必需的。然而，关于IL-1在控制肺炎肺炎的作用的知之甚少，这是一种与之相关的细胞内细菌 具有多种急性传染性过程，作为非典型肺炎，支气管炎和咽炎；肺炎梭菌的慢性感染也与包括动脉粥样硬化在内的多种慢性炎症态有关。 该提议的中心假设是肺炎梭状芽胞杆菌诱导的IL-1 Fiplays 在防御急性感染与慢性感染中的矛盾作用。我们的初步数据证明了 与其他相关衣原体不同的肺炎梭菌具有直接诱导鼠骨髓衍生的巨噬细胞的IL-1 ft分泌的独特能力，并且这种诱导取决于Nalp3/ASC炎症体络合物。我们认为，尽管IL-1（3在急性肺炎的分辨率中起重要作用，但其在慢性感染环境中的诱导促进了动脉粥样硬化斑块形成的特征的炎症。 为了进一步了解C. pnet/Mon/AE诱导的IL-IP在疾病发展中的作用，我们 提出以下特定目的：（1）定义感染肺炎梭菌感染的巨噬细胞诱导IL-1 P的分子机制； （2）检查急性细菌性肺炎和全身性炎症反应中IL-IP和IL-1受体的作用； （3）检查动脉粥样硬化特征的慢性炎症斑块形成中IL-IP和IL-1受体的作用。