Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly

检测

• 批准号: 8741915
• 负责人: Heather Winona Stout Delgado
• 金额: $ 21.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741915
• 关键词: Adult; Adverse effects; Age; Age-Years; Aging; Animal Model; Antibiotic Resistance; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological Assay; Biological Models; Caspase-1; Cell Culture Techniques; Cells; Clinical; Complex; Data; Dendritic Cells; Detection; Development; Disease; Early Intervention; Elderly; Gene Expression; Goals; Host Defense; Human; Hydroxyl Radical; Immune response; In Vitro; Infection; Inflammatory; Influenza; Interleukin-1; Interleukin-18; Interleukin-6; Ion Channel; Knowledge; Lead; Lung; Modeling; Molecular; Morbidity - disease rate; Mus; Nigericin; Outcome; Oxidative Stress; Patients; Persons; Pirfenidone; Pneumococcal Infections; Population; Preparation; Process; Production; Reporter; Role; Signal Pathway; Signal Transduction; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Testing; Therapeutic; Vaccination; Vaccines; Viral Pneumonia; Virus Diseases; Work; age effect; aging population; chemical property; cytokine; design; high risk; improved; improved functioning; in vivo; in vivo Model; insight; lung injury; macrophage; mortality; novel; novel therapeutics; public health relevance; response; screening; small molecule libraries; treatment strategy

DESCRIPTION (provided by applicant): Influenza viral infections and secondary pneumococcal infections are responsible for significant morbidity and mortality involving approximately five million people worldwide, with the highest infection rates found in the elderly (>65 years). It has been well established that innate and adaptive immune responses to influenza as well as Streptococcus pneumoniae are impaired with aging; however therapeutic treatments to augment these responses and thereby reduce high levels of mortality and morbidity in elderly hosts have not been well investigated. With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to investigate new therapeutics that can stimulate innate immune responses within this population. The NLRP3 inflammasome, a key signaling complex responsible for the processing and activation of IL-1¿ and IL-18, is activated in the lung during influenza viral infection by the M2 ion channel as well as during S. pneumoniae bacterial infection by pneumolysin. Our preliminary results demonstrate that elderly hosts have impaired inflammasome activation, decreased gene expression of several key components of the NLRP3 inflammasome signaling pathway, decreased caspase-1 activity and decreased IL-1¿ production in response to in vitro and in vivo infection with HKx31, a mouse adapted strain of influenza, and primary and secondary S. pneumoniae. Stimulation with ATP or nigericin, which have been previously shown to promote K+ efflux, augmented IL-1¿ expression by elderly dendritic cells (DC) as well as increased gene expression of NLRP3 inflammasome components and augmented caspase-1 activity during in vitro influenza as well as S. pneumoniae infection. Despite these findings, due to the chemical properties of ATP or nigericin, usage of these compounds may result in deleterious side effects in elderly hosts during pulmonary infections and hence there is a pressing need to investigate additional therapeutics. The goal of the proposed work is to investigate new compounds that, similar to ATP or nigericin, have the potential to stimulate NLRP3 inflammasome activation in elderly hosts and rescue function and improve clinical outcomes in elderly hosts. To this extent, in Aim 1, we will examine NLRP3 inflammasome function in response to an agent shown to alter oxidative stress, pirfenidone, as well as to search for additional compounds that can be used to heighten NLRP3 activity in elderly hosts during influenza infection (Aim 2). Specifically, we will employ a screen of chemical libraries to identify NLRP3 inflammasome activators that we will readily investigate using in vitro and in vivo murine models. We will test the hypothesis that an early intervention, such as stimulation of the NLRP3 inflammasome, in elderly hosts early during influenza or S. pneumoniae infection will improve innate immune responses and thereby decrease morbidity and mortality in this highly susceptible population. Summary and impact: As influenza infections and pneumococcal disease 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 investigate novel therapeutics and treatment strategies that reduce serious disease and improve clinical outcomes, in preparation for current and emergent strains of influenza or antibiotic resistant bacteria. Completion of the aims proposed in this R21 will further define the role of the NLRP3 inflammasome as an important innate signaling pathway during influenza and pneumococcal infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in additional model systems.

描述（由申请人提供）：流感病毒感染和继发性肺炎球菌感染是导致全球约500万人发病和死亡的主要原因，其中老年人（>65岁）的感染率最高。已经充分确定，对流感以及肺炎链球菌的先天性和适应性免疫应答随着衰老而受损;然而，用于增强这些应答从而降低老年宿主中的高水平死亡率和发病率的治疗性治疗尚未得到充分研究。随着人口老龄化和肺部感染成为发病率和死亡率的日益重要的原因，迫切需要研究可以刺激该人群中的先天免疫应答的新疗法。NLRP 3炎性体是一种负责IL-1和IL-18加工和激活的关键信号复合物，在流感病毒感染期间通过M2离子通道以及S.肺炎球菌溶血素引起的肺炎杆菌感染。我们的初步结果表明，老年宿主在体外和体内感染HKx 31（一种小鼠适应性流感病毒株）以及原发性和继发性S.肺炎。在体外流感和S.肺炎感染。尽管有这些发现，但由于ATP或尼日利亚菌素的化学性质，这些化合物的使用可能导致肺部感染期间老年宿主的有害副作用，因此迫切需要研究其他治疗方法。这项工作的目标是研究类似于ATP或尼日利亚菌素的新化合物，这些化合物有可能刺激老年宿主中的NLRP 3炎性小体激活，并挽救老年宿主的功能和改善临床结果。在这个程度上，在目标1中，我们将检查NLRP 3炎性小体响应于显示改变氧化应激的药剂吡非尼酮的功能，以及寻找可用于在流感感染期间提高老年宿主中NLRP 3活性的其他化合物（目标2）。具体来说，我们将使用一种化学物质 库来鉴定NLRP 3炎性体激活剂，我们将很容易使用体外研究 和体内鼠模型。我们将检验这样的假设，即在老年宿主中，在流感或链球菌感染的早期进行早期干预，如刺激NLRP 3炎性小体。肺炎链球菌感染将改善先天免疫应答，从而降低该高度易感人群的发病率和死亡率。摘要和影响：由于流感感染和肺炎球菌疾病仍然是老年人发病率和死亡率的主要原因，即使在常规成人疫苗接种的时代，迫切需要研究新的治疗方法和治疗策略，以减少严重疾病并改善临床结果，为当前和新出现的流感菌株或抗生素耐药性细菌做好准备。该R21中提出的目标的完成将进一步定义NLRP 3炎性体作为流感和肺炎球菌感染期间重要的先天信号传导途径的作用，以及产生可以在原代人类细胞中容易地测试并在其他模型系统中评估的新疗法。