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

细胞外腺苷在年龄驱动的肺炎链球菌肺部感染易感性中的作用

• 批准号: 9793990
• 负责人: Elsa Bou Ghanem
• 金额: $ 23.68万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9793990
• 关键词: 5' -Nucleotidase; Adenosine; Adoptive Transfer; Age; Aging; Agonist; Animal Model; Area; Automobile Driving; Award; Bacteremia; Bacterial Infections; Bacterial Pneumonia; Biological Assay; Biology of Aging; Brain; Cardiac; Cell physiology; Cells; Data; Defect; Disease; Drug Targeting; Economic Burden; Elderly; Endothelial Cells; Endothelium; Environment; Enzymes; Faculty; Functional disorder; Goals; Hour; Immune; Impairment; In Vitro; Infection; Infection Control; Infiltration; Inflammaging; Inflammation; Inflammatory; Institutes; Lead; Learning; Life; Link; Lung; Lung infections; Measures; Mediating; Meningitis; Mentors; Metabolic; Metabolism; Modeling; Monitor; Mus; Organ; Outcome; Paper; Pathway interactions; Phase; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumonia; Positioning Attribute; Predisposition; Production; Publishing; Pulmonary Inflammation; Purinergic P1 Receptors; Research; Resources; Role; Septicemia; Signal Transduction; Streptococcus pneumoniae; Techniques; Time; TimeLine; United States; Universities; adenosine deaminase; age related; aged; bacterial resistance; base; combat; design; experimental study; extracellular; health economics; immunosenescence; in vivo; infectious disease model; injured; innovation; lung injury; migration; monolayer; mouse model; neutrophil; novel; public health relevance; receptor; recruit; response

 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.

 描述（由适用提供）：侵袭性肺炎链球菌（肺炎球菌）感染，例如肺炎，细菌和脑膜炎，在美国造成了考虑的健康和经济灼伤。这要求更好地理解驱动老年宿主免疫失调的潜在途径，从而使其容易感染感染。我的长期目标是在学术环境中领导一个研究小组，探讨细胞外腺苷（EAD）途径的变化，炎症的主要调节剂及其对衰老宿主对肺炎链球菌感染的敏感性增强的贡献。背景：肺炎链球菌感染后疾病进程的重要因素是多形核白细胞 - （PMNS-）。我们发现最初需要PMN来控制细菌数量，但是，炎症性PMN的扩展存在导致严重的肺损伤和对感染的控制不良。在寻找感染的调节剂时，我们发现，EAD是由胞外酶CD73和CD39从受伤细胞泄漏的ATP崩溃而产生的，并通过四个腺苷受体介导了其作用，靶向PMN功能和年轻小鼠中肺炎球菌感染期间PMN功能和肺部招募。当我们对年龄相关的肺炎链球菌的敏感性建模时，我们发现年龄小鼠非常容易受到侵入性肺炎球菌感染的影响，并且易感性与PMN和PMN的肺炎球菌杀伤受损有关，并增强了肺部PMN招募。这导致了以下假设：衰老时EAD途径的失调导致PMN功能受损和肺部PMN影响的加剧，并导致与年龄相关的肺炎链球菌感染的敏感性。我将使用老化的鼠模型来表征肺炎链球菌感染期间EAD途径的变化，其对PMN反应中年龄驱动的失调的影响以及年龄驱动的细菌易感性。意义和创新：阐明随着年龄的增长，在EAD途径中发生变化的可能性有可能揭示新的途径，这些途径可以使用易于使用的基于腺苷的疗法来促进免疫力，并导致可行的策略，以减轻对细菌肺炎的抗年龄相关的耐药性下降。时间表：由于我是老化领域的新手，指导的K99阶段将为我提供利用塔夫茨大学独特机会所需的时间和资源，包括与我的两个导师DR的密切互动。 John Leong和Simin Meydani是免疫疾病的免疫衰老和动物建模专家，参与Tufts倡议的健康和积极衰老的参与以及衰老的生物学课程，以进一步获得该领域的专业知识。我还将学习使该项目可行的技术，发表更多论文并过渡到独立性，包括两年内该奖项的R00阶段的申请以及学术机构的独立教师职位。