Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung

UPR 激活增强对老年肺中流感和继发性肺炎链球菌感染炎症反应的影响

• 批准号: 10207433
• 负责人: Heather Winona Stout Delgado
• 金额: $ 37.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207433
• 关键词: ATF6 gene; Adult; Age; Aging; Animal Model; Bacterial Antibiotic Resistance; Bacterial Infections; Biological Aging; Biological Models; CASP1 gene; Cell Culture Techniques; Cells; Clinical; Complex; Data; Defect; Disease; Edema; Elderly; Endoplasmic Reticulum; Functional disorder; Gene Expression; Genetic Transcription; Homeostasis; Human; IL18 gene; Immune; Immune response; Impairment; In Vitro; Infection; Inflammasome; Inflammation; Influenza; Innate Immune Response; Interleukin-1 beta; Knowledge; Link; Lung; Lung infections; Mediating; Mediator of activation protein; Mitochondria; Molecular; Morbidity - disease rate; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pneumococcal Infections; Population; Predisposition; Process; Production; Proteins; Regulation; Regulatory Pathway; Research Proposals; Role; Secondary to; Signal Pathway; Signal Transduction; Stimulus; Streptococcus pneumoniae; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Vaccination; Viral Pathogenesis; Virulence; Virus Diseases; Work; adaptive immune response; aged; aging population; design; endoplasmic reticulum stress; experimental study; improved; in vivo; infection rate; influenza infection; influenza pneumonia; innovation; lung injury; mitochondrial dysfunction; mortality; mouse model; novel therapeutics; pathogen; programs; protein expression; response; sensor; therapeutic evaluation; tissue injury; treatment strategy; young adult

Project Summary With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics that can stimulate innate immune responses within this population. Our results demonstrate aged hosts have impaired inflammasome activation, decreased gene expression of several key components of the NLRP3 signaling pathway, reduced caspase-1 activity, and diminished IL1β production in response to in vitro and in vivo infection with influenza or S. pneumoniae. Using in vitro and in vivo aging murine models of primary influenza and secondary S. pneumoniae infection, we will employ cellular and molecular techniques to test our overall hypothesis that the NLRP3 inflammasome is necessary for survival and age associated impairments in ER and mitochondrial Ca2+ homeostasis result in impaired activation of the NLRP3 inflammasome in aged lung; thereby, resulting in increased pathogenesis, tissue injury, and pneumonic edema in the elderly lung. To test this hypothesis, we will examine the role of the unfolded protein response (UPR) on inflammasome activity in response to influenza (Aim 1) and the impact of overly heightened pathogenic mediated UPR on inflammasome activation in response to secondary S. pneumoniae infection (Aim 2). Summary and impact: As pulmonary pneumococcal infections remain a substantial cause of morbidity and mortality in the elderly, even in an era of routine adult vaccination, there is a pressing need to identify mechanistic pathways that regulate innate immune responses and investigate novel therapeutics and treatment strategies that reduce serious disease and improve clinical outcomes. By establishing and dissecting a pivotal mechanistic link between UPR activation and inflammasome signaling in aged lung, this research proposal has high potential to elucidate innovative regulatory pathways and expand current understanding of age associated changes in ER homeostasis. Therapeutic strategies designed to target defects in innate signaling in the aged host will aid in circumventing emergent strains of antibiotic resistant bacteria and may be utilized for treatment against a wide variety of pathogenic stimuli. Completion of the proposed aims will further define the role of the NLRP3 inflammasome as an important innate signaling pathway during influenza and secondary S. pneumoniae infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in additional model systems.

项目概要 随着人口老龄化和肺部感染成为发病率和发病率日益重要的原因 死亡率，迫切需要研究这些损伤背后的分子途径并设计 我们的研究结果表明，新疗法可以刺激该人群的先天免疫反应。 老年宿主的炎症小体激活受损，几个关键成分的基因表达降低 NLRP3 信号通路，降低 caspase-1 活性，并减少 IL1β 的产生，以响应 使用流感或肺炎链球菌的体外和体内衰老小鼠模型。 原发性流感和继发性肺炎链球菌感染，我们将利用细胞和分子技术来 检验我们的总体假设，即 NLRP3 炎性体对于生存和年龄相关是必需的 ER 和线粒体 Ca2+ 稳态受损导致 NLRP3 激活受损 老化肺中的炎症小体；导致发病机制增加、组织损伤，从而导致肺水肿 为了验证这一假设，我们将研究未折叠蛋白反应（UPR）对老年肺部的影响。 流感反应中的炎症小体活动（目标 1）以及过度呼吸道致病菌的影响 介导 UPR 对继发性肺炎链球菌感染的炎症小体激活的反应（目标 2）。 摘要和影响：由于肺肺炎球菌感染仍然是发病率和死亡率的一个重要原因， 即使在成人常规接种疫苗的时代，也迫切需要确定老年人的死亡率 调节先天免疫反应并研究新疗法的机制途径 通过建立和剖析减少严重疾病并改善临床结果的治疗策略。 这项研究揭示了老年肺中 UPR 激活和炎症小体信号传导之间的关键机制联系 该提案具有很大的潜力来阐明创新的监管途径并扩大目前对 针对先天缺陷而设计的治疗策​​略与年龄相关。 衰老宿主中的信号传导将有助于规避新出现的抗生素耐药细菌菌株，并且可能是 用于治疗多种致病刺激将进一步完成所提出的目标。 定义 NLRP3 炎性体作为流感和流感期间重要的先天信号通路的作用 继发性肺炎链球菌感染，并产生可在原发性肺炎中轻松测试的新疗法 人类细胞和其他模型系统中的评估。