Age-associated inflammation increases susceptibility to pneumococcal infection

描述(由申请人提供)： 衰老与炎症增加有关；炎症是一系列因素的结果，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)附着和侵袭的必要条件；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起病快、严重、死亡率高，因此我们推测年龄相关性炎症(AAI)发生在肺部，是老年人侵袭性肺炎球菌病(IPD)的易感因素。这一假说基于以下观察：1)老年人经历了轻度慢性炎症，其特征是组织中NFkB激活水平和血液中促炎症细胞因子水平升高。2)老年人有感染肺炎球菌的风险，并且他们的风险随着基础条件的加强而增加。3)肺炎球菌配体聚合免疫球蛋白受体(PIgR)和血小板活化因子受体(PAFR)对NFkB的激活有反应，并在接触促炎细胞因子后上调/表达。4)肺炎链球菌与pIgR和/或PAFR结合，并利用这些蛋白入侵细胞并转移到血液中。最后，老年人和老年小鼠感染肺炎链球菌的特点是严重感染，组织损伤更多，肺实变，细菌负荷更高，死亡率更高。为了验证我们的假设，我们将：目标1：确定AAI是否发生在健康老年小鼠的肺中。A)测量肺中NFkB激活和促炎细胞因子的水平。B)测量肺部的pIgR和PAFR水平。C)确定长期暴露于低水平的TNF1或IL-6是否会增加肺中pIgR/PAFR的表达。目的2：确定肺炎链球菌攻击的老年小鼠是否经历了免疫反应失调，以及这种反应是否导致组织损伤。A)检测感染老年小鼠的NFkB活性、细胞因子和白细胞渗透水平。B)检测感染老年小鼠肺组织ICAM-1、P-选择素、pIgR和PAFR水平。C)确定长期暴露于TNF1或IL-6是否会增加幼鼠对肺炎链球菌的易感性。--衰老与炎症增加和对IPD的易感性有关。这笔赠款将确定这些观察到的现象之间是否存在联系。--

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. --