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.

寄主感知病原生物入侵并对控制作出适当反应的能力 感染对生存至关重要然而，在某些情况下，过度的炎症反应可导致旁观者损伤和全身炎症症状，可能导致与压倒性感染相关的发病率和死亡率。促炎细胞因子白细胞介素（IL）-1是宿主防御各种感染状态的关键介质。例如，IL-1在脂多糖的气管内给药后在肺中产生，并且其存在与肺炎中的肺部炎症和细菌负荷直接相关。IL-1是控制多种细胞内病原体如李斯特菌、利什曼原虫和结核分枝杆菌所必需的。然而，关于IL-1在控制嗜肺炎衣原体中的作用知之甚少，嗜肺炎衣原体是一种专性细胞内细菌，与肺炎衣原体相关。 急性感染如非典型肺炎、支气管炎、咽炎等;肺炎还与包括动脉粥样硬化在内的多种慢性炎症状态有关。 这个建议的中心假设是C。肺炎诱导的IL-1纤维 在急性与慢性感染的防御中的矛盾作用。我们的初步数据显示 梭与其它相关衣原体物种不同，肺炎衣原体具有直接诱导来自鼠骨髓来源的巨噬细胞的IL-1 β分泌的独特能力，并且这种诱导依赖于NALP 3/ASC炎性体复合物。我们认为，虽然IL-1 β在急性肺炎的消退中起重要作用，但其在慢性感染环境中的诱导有助于炎症，而炎症是动脉粥样硬化斑块形成的特征。 为了进一步了解C. pnet/mon/ae诱导的IL-1 β在疾病发展中的作用， 本研究的主要目的是：（1）阐明巨噬细胞感染C.肺炎;（2）研究IL-1 β和IL-1受体在急性细菌性肺炎和全身炎症反应中的作用;（3）研究IL-1 β和IL-1受体在动脉粥样硬化特征性慢性炎性斑块形成中的作用。