The role of extracellular adenosine in age-driven susceptibility to S. pneumoniae lung infection

 描述(由申请人提供)：侵袭性肺炎链球菌(肺炎球菌)感染老年人，如肺炎、菌血症和脑膜炎，在美国造成相当大的健康和经济负担。这需要更好地理解导致老年宿主免疫失调的潜在途径，使他们更容易受到感染。我的长期目标是领导一个学术环境的研究小组，探索炎症的主要调节因素-细胞外腺苷(EAD)途径的年龄驱动变化，以及它对老年宿主对肺炎链球菌感染的易感性增加的贡献。背景：肺炎链球菌肺部感染后病程的一个重要因素是中性粒细胞(PMNS-)。我们发现，PMN最初是控制细菌数量所必需的，然而，炎症性PMN的长期存在会导致严重的肺损伤和对感染的不良控制。在寻找炎症调节因子的过程中，我们发现EAD是由胞外酶CD73和CD39分解受损细胞中泄漏的ATP产生的，并通过四种腺苷受体介导其作用，在肺炎球菌感染的幼鼠中针对PMN功能和肺募集。当我们对肺炎链球菌与年龄相关的易感性进行建模时，我们发现老年小鼠对侵袭性肺炎球菌感染高度敏感，而且这种易感性与PMN对肺炎球菌的杀伤作用减弱和肺PMN募集的增强有关。这导致了一种假设：随着年龄的增长，EAD途径的失调会导致PMN功能受损和肺部PMN流入的加剧，并导致与年龄相关的肺炎链球菌感染的易感性。我将使用老年小鼠模型描述肺炎链球菌感染过程中EAD途径的变化，它对年龄驱动的PMN反应失调和年龄驱动的细菌性肺炎易感性的影响。意义和创新：阐明EAD途径中随年龄发生的变化有可能发现驱动免疫衰老的新途径，并导致使用现成的基于腺苷的疗法来缓解与年龄相关的细菌性肺炎抵抗力下降的可行策略。时间表：由于我对老龄化领域非常陌生，导师K99阶段将为我提供所需的时间和资源，以利用在塔夫茨大学的独特机会，包括与我的两位导师梁约翰博士和Simin Meydani博士的密切互动，他们是免疫衰老和传染病动物模型方面的专家，参与塔夫茨的健康和积极老龄化倡议，以及老龄生物学课程，以进一步获得该领域的专业知识。我还将学习使这个项目可行所需的技术，发表更多的论文并过渡到独立，包括在两年内申请这个奖项的R00阶段，以及申请学术机构的独立教职。

 DESCRIPTION (provided by applicant): Invasive Streptococcus pneumoniae (pneumococcus) infections in the elderly, such as pneumonia, bacteremia, and meningitis, create a considerable health and economic burden in the United States. This calls for a better understanding of the underlying pathways driving immune dysregulation in aged hosts rendering them susceptible to infections. My long-term goal is to lead a research group in an academic setting exploring the age-driven changes in the extracellular adenosine (EAD) pathway, a major regulator of inflammation, and its contribution to the heightened susceptibility of aged hosts to S. pneumoniae infection. Background: An important contributor to the course of disease following S. pneumoniae lung infection is polymorphonuclear leukocytes- (PMNs-). We found that PMNs are initially required for controlling bacterial numbers, however, extended presence of inflammatory PMNs led to significant lung damage and poor control of infection. In searching for regulators of inflammation, we found that EAD, that is produced from breakdown of ATP leaking from injured cells by the ectoenzymes CD73 and CD39 and mediates its action via four adenosine receptors, targets both PMN function and pulmonary recruitment during pneumococcal infection in young mice. When we modeled age-associated susceptibility to S. pneumoniae, we found that aged mice are highly susceptible to invasive pneumococcal infection and that susceptibility was linked to impairment of pneumococcal killing by PMNs and enhancement of pulmonary PMN recruitment. This led to the Hypothesis that: dysregulation of the EAD pathway upon aging results in both impairment in PMN function and exacerbation of pulmonary PMN influx and contributes to the age-associated susceptibility to S. pneumoniae infection. I will characterize the changes in the EAD pathway during S. pneumoniae infection using an aged murine model, its effect on age-driven dysregulation in PMN responses and age-driven susceptibility to bacterial pneumonia. Significance and innovation: Elucidating the changes occurring in the EAD pathway with age has the potential to uncover novel pathways that drive immunosenescence and lead to feasible strategies using readily available adenosine-based therapies to to mitigate the age-associated decline in resistance to bacterial pneumonia. Timeline: As I am very new to the aging field, the mentored K99 phase will provide me the time and resources needed to take advantage of the unique opportunities at Tufts University including close interaction with my two mentors Drs. John Leong and Simin Meydani who are experts in immunosenescence and animal modeling of infectious diseases, involvement in the Healthy and Active Aging at Tufts initiative and courses in the biology of aging to further gain expertise in this area. I will also learn the techniques required to make this project feasible, publish more papers and transition to independence including application for the R00 phase of this award within two years and for independent faculty positions at academic institutes.