Analyzing the role of the aging microbiota in susceptibility to Streptococcus pneumoniae

分析衰老微生物群在肺炎链球菌易感性中的作用

• 批准号: 290129999
• 负责人: Dr. Christian Schulz
• 金额: --
• 依托单位: Department of Pathology and Molecular Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290129999?language=en
• 关键词: Analyzing; role; aging; microbiota; susceptibility

Human life expectancy continues to increase worldwide and consequently the proportion of elderly individuals (defined as persons age 65 or older) is increasing. Germany is affected by the demographic transition in particular, having the second highest median age worldwide (44.3 years). Public spending, especially with regard to health care costs, must adapt to the health care needs of a rapidly aging demographic, as the susceptibility for diseases increases with age due to a declining immune system. Recent work from the Bowdish lab has shown that chronic age-associated inflammation impairs macrophage function. Macrophages are key players of the innate immune system and therefore the first line of defense against infectious diseases, such as community-acquired pneumonia - commonly caused by Streptococcus pneumoniae (pneumococcus). S. pneumoniae is a common, transient and generally asymptomatic member of the microbiota of the upper respiratory tract (URT) in children. In contrast, colonization of the URT in elderly occurs less frequently, but results in infection regularly. Preliminary data obtained in the Bowdish lab showed that the composition of mouse and human URT microbiota becomes dysregulated with age and inflammation. This data indicates that the changing microbiota, chronic inflammation and changing innate immune responses in the elderly synergize to increase the risk of pneumococcal infection. To test this, I will analyze how the composition of the microbiome affects susceptibility for pneumococcal infection using a unique mouse model well established in the Bowdish lab. To investigate whether young microbiota protect against S. pneumoniae infection, young (3 mos.) or old (>18 mos.) germ-free mice will be colonized with the microbiota of young or old conventionally housed SPF (specific pathogen free) mice. After infection of the mice with S. pneumoniae, I will evaluate their immune status by quantifying bacterial numbers in and leukocyte infiltration to the nasopharynx, cytokines in the blood, as well as mobilization and maturation of circulating monocytes. To subsequently elucidate the influence of the aged microbiota on the immune system in more detail, germ-free mice will be exposed to young, respectively old microbiota. By measuring cytokine levels and bacterial components in the blood, the intestinal permeability, and the macrophage function (sentinel cells of the URT), I will obtain information about how the microbiota affect immune function and inflammation. Results of this study will elucidate how synergy between the aging immune system and microbial dysbiosis contributes to pneumococcal infection and provide novel avenues of therapeutic interventions such as targeting microbial dysbiosis.

全世界人类的预期寿命继续延长，因此老年人（定义为65岁或以上的人）的比例也在增加。德国尤其受到人口结构转型的影响，它的中位年龄在世界上排名第二（44.3岁）。公共开支，特别是保健费用方面的开支，必须适应人口迅速老龄化的保健需要，因为随着年龄的增长，由于免疫系统下降，对疾病的敏感性增加。Bowdish实验室最近的工作表明，慢性年龄相关性炎症损害巨噬细胞功能。巨噬细胞是先天免疫系统的关键参与者，因此是预防感染性疾病的第一道防线，例如社区获得性肺炎-通常由肺炎链球菌（肺炎球菌）引起。S.肺炎是儿童上呼吸道（URT）微生物群中常见的、短暂的且通常无症状的成员。相比之下，在老年人的URT定植发生频率较低，但经常导致感染。Bowdish实验室获得的初步数据显示，小鼠和人类URT微生物群的组成随着年龄和炎症而失调。这些数据表明，老年人不断变化的微生物群，慢性炎症和不断变化的先天免疫反应协同作用，增加了肺炎球菌感染的风险。为了验证这一点，我将使用Bowdish实验室建立的独特小鼠模型分析微生物组的组成如何影响肺炎球菌感染的易感性。为了研究年轻的微生物群是否能抵抗S。肺炎感染，年轻（3个月）或老年人（>18个月）无菌小鼠将用年轻或年老的常规饲养的SPF（无特定病原体）小鼠的微生物群定殖。小鼠感染S.对于肺炎患者，我将通过定量鼻咽部中的细菌数量和白细胞浸润、血液中的细胞因子以及循环单核细胞的动员和成熟来评估其免疫状态。为了随后更详细地阐明老年微生物群对免疫系统的影响，将无菌小鼠分别暴露于年轻微生物群和老年微生物群。通过测量血液中的细胞因子水平和细菌成分、肠道渗透性和巨噬细胞功能（URT的哨兵细胞），我将获得有关微生物群如何影响免疫功能和炎症的信息。这项研究的结果将阐明衰老的免疫系统和微生物生态失调之间的协同作用如何有助于肺炎球菌感染，并提供新的治疗干预途径，如靶向微生物生态失调。