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.

项目摘要 随着人口老龄化和肺部感染成为发病率和 死亡率，迫切需要研究这些损伤背后的分子途径，并设计 可以刺激这一人群的先天免疫反应的新疗法。我们的结果表明 老年宿主炎性小体激活受损，几个关键成分基因表达减少 NLRP3信号通路，降低caspase-1活性，减少IL-1β的产生 在体外和体内感染流感或肺炎链球菌。体外和体内衰老小鼠模型的建立 对于原发流感和继发性肺炎链球菌感染，我们将使用细胞和分子技术来 测试我们的总体假设，即NLRP3炎症体对于生存和年龄相关是必要的 内质网和线粒体钙稳态受损导致NLRP3激活受损 老年肺中的炎症性小体；从而导致发病机制加重、组织损伤和肺水肿。 在老年人的肺里。为了验证这一假设，我们将检查未折叠蛋白反应(UPR)在 流感反应中的炎症体活动(目标1)和致病性过度增强的影响 介导UPR对肺炎链球菌继发感染后炎性小体激活的影响(目标2)。 摘要和影响：由于肺部肺炎球菌感染仍然是发病率和死亡率的主要原因 老年人的死亡率，即使在成人常规接种疫苗的时代，也迫切需要确定 调节先天免疫反应和研究新疗法和 减少严重疾病和改善临床结果的治疗策略。通过建立和剖析 老年肺组织中UPR激活和炎症体信号之间的关键机制联系，这项研究 提案有很高的潜力阐明创新的监管途径并扩大目前对 与年龄相关的内质网稳态变化。针对先天缺陷的治疗策略 老年宿主中的信号将有助于绕过新出现的抗药性细菌菌株，并可能 用于治疗各种致病刺激。完成拟议的目标将进一步 明确NLRP3炎症体在流感和流感期间作为重要的先天信号通路的作用 继发性肺炎链球菌感染，以及产生新的治疗方法，可以很容易地在初级 并在其他模型系统中进行评估。