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的日益重要的原因， 死亡率，迫切需要调查这些损伤的分子途径，并设计 新的疗法可以刺激这一人群的先天免疫反应。我们的研究结果表明 老年宿主炎性小体活化受损， NLRP 3信号通路，降低caspase-1活性，减少IL-1 β的产生。 体外和体内感染流感或S.肺炎。使用体外和体内衰老小鼠模型， 原发性流感和继发性S.肺炎感染，我们将采用细胞和分子技术， 检验我们的总体假设，即NLRP 3炎性小体对于生存和年龄相关性是必需的。 ER和线粒体Ca 2+稳态的损伤导致NLRP 3的活化受损 老年肺中的炎性小体;从而导致发病率增加、组织损伤和肺水肿 在老年人的肺里为了验证这一假设，我们将研究未折叠蛋白反应（UPR）对 炎症体活性对流感的反应（目的1）和过度升高的致病性 介导的UPR对继发性S.肺炎感染（目的2）。 摘要和影响：由于肺部肺炎球菌感染仍然是发病的主要原因， 老年人的死亡率，即使在常规成人疫苗接种的时代，也迫切需要确定 调节先天免疫反应的机制途径，并研究新的治疗方法， 减少严重疾病和改善临床结果的治疗策略。通过建立和解剖 一个关键的机制之间的联系UPR激活和炎症信号在老年肺，这项研究 该提案具有很大的潜力，可以阐明创新的监管途径，并扩大目前对 ER稳态的年龄相关变化。针对先天性缺陷的治疗策略 老年宿主中的信号传导将有助于规避抗生素抗性细菌的新菌株， 用于治疗多种致病性刺激。实现拟议目标将进一步 定义NLRP 3炎性体作为流感期间重要的先天信号传导途径的作用， 次级S.肺炎感染，以及产生新的治疗方法，可以很容易地在原发性 人细胞并在另外的模型系统中评估。