Age-associated inflammation increases susceptibility to pneumococcal infection

与年龄相关的炎症增加对肺炎球菌感染的易感性

• 批准号: 7502167
• 负责人: Carlos J Orihuela
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502167
• 关键词: Adhesions; Age; Age-Years; Aging; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Bacteremia; Binding; Blood; Blood Circulation; Brain; Cause of Death; Cell physiology; Cells; Chronic; Communities; Condition; Cytokine Activation; Data; Disease Outcome; Elderly; Environmental Exposure; Exposure to; Feedback; Goals; Grant; Heart; Human; Immune response; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-6; Intervention; Invaded; Invasive; Kidney; Leukocytes; Ligands; Link; Liver; Lung; Measures; Mus; Numbers; P-Selectin; Personal Satisfaction; Pharmaceutical Preparations; Pneumococcal Infections; Pneumonia; Polymeric Immunoglobulin Receptors; Population; Predisposition; Preventive Medicine; Proteins; Range; Rate; Respiratory Tract Infections; Risk; Serum; Severities; Streptococcus pneumoniae; Testing; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; age related; aged; base; cytokine; environmental agent; experience; healthy aging; human TNF protein; improved; in vivo; leukocyte activation; mortality; platelet activating factor receptor; receptor expression; response; senescence

DESCRIPTION (provided by applicant): Aging is associated with increased inflammation; inflammation the result of a wide range of factors including dysregulation of senescent cells, environmental exposures, and age-associated illnesses. Inflammation is also requisite for Streptococcus pneumoniae (the pneumococcus) attachment and invasion; the pneumococcus being a leading cause of death in the elderly. Pneumococcal disease in the elderly is characterized by its rapid onset, severity, and high-mortality rate; thus we hypothesize that age-associated inflammation (AAI) occurs in the lungs and predisposes the elderly for invasive pneumococcal disease (IPD). This hypothesis is based on the following observations: 1) That the elderly experience low-grade chronic inflammation characterized by elevated levels of NFkB activation in tissues and pro-inflammatory cytokines in the blood. 2) That the elderly are at risk for pneumococcal infection and that their risk increases with underlying conditions that enhance inflammation. 3) That the pneumococcal ligands polymeric immunoglobulin receptor (pIgR) and platelet activating factor receptor (PAFr) are responsive to NFkB activation and are up- regulated/expressed following exposure to pro-inflammatory cytokines. 4) That S. pneumoniae binds to pIgR and/or PAFr and uses these proteins to invade cells and translocate to the bloodstream. And finally, 5) that infection of elderly humans and aged mice with S. pneumoniae is characterized by severe infection with more tissue damage, lung consolidation, higher bacterial burden, and mortality than the young. To test our hypothesis we will: Aim 1: Determine if AAI occurs in the lungs of healthy aged mice. A) Measure levels of NFkB activation and pro-inflammatory cytokines in the lungs. B) Measure pIgR and PAFr levels in the lungs. C) Determine if prolonged exposure to low levels of TNF1 or IL-6 increases pIgR/PAFr expression in the lungs. Aim 2: Determine if aged mice challenged with S. pneumoniae experience a dysregulated immune response and if the response contributes to tissue damage. A) Measure levels of NFkB activation, cytokines, and leukocyte infiltration in infected aged mice. B) Measure ICAM-1, P-selectin, pIgR, and PAFr levels in the lungs of infected aged mice. C) Determine if prolonged exposure to TNF1 or IL-6 increases susceptibility of young mice to S. pneumoniae. -- Aging is associated with increased inflammation and susceptibility to IPD. This grant will determine if a link exists between these observed phenomena. --

描述（由申请人提供）： 衰老与炎症增加有关;炎症是多种因素的结果，包括衰老细胞的失调，环境暴露和与年龄相关的疾病。炎症也是肺炎链球菌（肺炎球菌）附着和侵入所必需的;肺炎球菌是老年人死亡的主要原因。老年人肺炎球菌病的特点是发病迅速、严重和死亡率高;因此，我们假设年龄相关性炎症（AAI）发生在肺部，使老年人易患侵袭性肺炎球菌病（IPD）。该假设基于以下观察：1）老年人经历以组织中的NFkB活化和血液中的促炎细胞因子水平升高为特征的低度慢性炎症。2)老年人有肺炎球菌感染的风险，并且他们的风险随着增强炎症的基础条件而增加。3)肺炎球菌配体多聚免疫球蛋白受体（pIgR）和血小板活化因子受体（PAFr）对NF κ B活化有反应，并在暴露于促炎细胞因子后上调/表达。4)那辆多肺炎链球菌与pIgR和/或PAFr结合，并利用这些蛋白质侵入细胞并易位至血流。最后，5）老年人和老年小鼠感染S。肺炎的特征是严重感染，与年轻人相比，有更多的组织损伤、肺实变、更高的细菌负荷和死亡率。为了验证我们的假设，我们将：目的1：确定AAI是否发生在健康老年小鼠的肺部。A）测量肺部NFkB激活和促炎细胞因子的水平。B）测量肺中的pIgR和PAFr水平。C）确定长期暴露于低水平TNF 1或IL-6是否增加肺中的pIgR/PAFr表达。目的2：确定是否用S.肺炎患者会经历免疫反应失调，并且该反应是否会导致组织损伤。A）测量感染的老年小鼠中NFkB活化、细胞因子和白细胞浸润的水平。B）测量感染的老年小鼠肺中的ICAM-1、P-选择素、pIgR和PAFr水平。C）确定长期暴露于TNF 1或IL-6是否会增加年幼小鼠对S.肺炎。--衰老与炎症增加和对IPD的易感性有关。这项赠款将确定这些观察到的现象之间是否存在联系。--