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

世界各地的人的预期寿命继续增加，因此老年人(定义为65岁或65岁以上的人)的比例也在增加。德国尤其受到人口结构转变的影响，德国的中位年龄位居世界第二(44.3岁)。公共支出，特别是在保健费用方面，必须适应快速老龄化人口的保健需求，因为由于免疫系统下降，疾病的易感性随着年龄的增长而增加。Bowish实验室最近的研究表明，与年龄相关的慢性炎症会损害巨噬细胞的功能。巨噬细胞是先天免疫系统的关键参与者，因此是抵御传染病的第一道防线，例如社区获得性肺炎--通常由肺炎链球菌(肺炎球菌)引起。肺炎链球菌是一种常见的、短暂的、通常无症状的儿童上呼吸道(URT)微生物区系成员。相比之下，城市轨道交通在老年人中的定植较少发生，但会导致经常性的感染。鲍迪什实验室获得的初步数据显示，随着年龄和炎症的增加，小鼠和人类URT微生物区系的组成变得失调。这一数据表明，老年人不断变化的微生物区系、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。为了测试这一点，我将使用Bowish实验室建立的独特的小鼠模型来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对肺炎链球菌的感染有保护作用，Young(3mos.)或旧(&gt；18个月)无菌小鼠将与传统饲养的SPF(无特定病原体)小鼠的微生物群一起定居。在小鼠感染肺炎链球菌后，我将通过量化鼻咽中的细菌数量和白细胞向鼻咽的渗透，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它们的免疫状态。为了随后更详细地阐明老化的微生物群对免疫系统的影响，无菌小鼠将分别暴露在年轻的和老年的微生物群中。通过测量血液中的细胞因子水平和细菌成分、肠道通透性和巨噬细胞功能(URT的哨兵细胞)，我将获得有关微生物区系如何影响免疫功能和炎症的信息。这项研究的结果将阐明老化的免疫系统和微生物失调之间的协同作用如何有助于肺炎球菌感染，并为治疗干预提供新的途径，如靶向微生物失调。

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.