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

 描述（由申请人提供）：在美国，老年人中的侵袭性肺炎链球菌（肺炎球菌）感染，如肺炎、菌血症和脑膜炎，造成相当大的健康和经济负担。这需要更好地理解驱动老年宿主免疫失调的潜在途径，使其易于感染。我的长期目标是在学术环境中领导一个研究小组，探索细胞外腺苷（EAD）通路的年龄驱动变化，这是炎症的主要调节因子，以及它对老年宿主对S.肺炎感染。背景：一个重要的贡献者疾病的过程中，以下S。肺炎肺部感染是多形核白细胞（PMNs）。我们发现，中性粒细胞最初需要控制细菌数量，然而，炎性中性粒细胞的长期存在导致显着的肺损伤和感染控制不良。在寻找炎症调节因子的过程中，我们发现EAD是由胞外酶CD 73和CD 39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，它靶向年轻小鼠肺炎球菌感染期间的PMN功能和肺募集。当我们模拟年龄相关的S。通过对肺炎链球菌感染小鼠的研究，我们发现老年小鼠对侵袭性肺炎球菌感染高度易感，并且易感性与中性粒细胞对肺炎球菌的杀伤能力受损和肺中性粒细胞募集的增强有关。这导致了以下假说：随着年龄的增长，EAD通路的失调导致了PMN功能的损害和肺PMN内流的加剧，并有助于与年龄相关的S。肺炎感染。我将描述S.使用老年鼠模型，研究了其对年龄驱动的PMN应答失调和年龄驱动的细菌性肺炎易感性的影响。意义与创新：阐明EAD途径随着年龄的增长而发生的变化有可能发现驱动免疫衰老的新途径，并使用现成的基于腺苷的疗法制定可行的策略，以缓解与年龄相关的细菌性肺炎抵抗力下降。时间轴：由于我对衰老领域非常陌生，指导K99阶段将为我提供所需的时间和资源，以利用塔夫茨大学的独特机会，包括与我的两位导师John Leong博士和Simin Mekanani博士的密切互动，他们是免疫衰老和传染病动物模型的专家，参与塔夫茨大学的健康和积极老龄化倡议和老龄化生物学课程，以进一步获得这一领域的专业知识。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，包括在两年内申请该奖项的R00阶段，并在学术机构的独立教师职位。

 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.