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

检测

基本信息

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
项目类别：
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

项目摘要

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导致全世界约 500 万人发病和死亡，其中老年人（> 65 岁）的感染率最高。已明确先天感染。对流感和肺炎链球菌的适应性免疫反应会随着年龄的增长而减弱；然而，增强这些反应从而降低老年宿主高死亡率和发病率的治疗方法尚未得到充分研究。人口老龄化和肺部感染日益成为发病和死亡的重要原因，迫切需要研究能够刺激该人群先天免疫反应的新疗法，NLRP3 炎症小体是负责处理和激活炎症的关键信号复合物。 IL-1??和IL-18，在流感病毒感染期间被M2离子通道激活，以及在肺炎链球菌感染期间被肺炎球菌溶血素激活。我们的初步结果表明，老年宿主炎症小体激活受损，几个关键成分的基因表达降低。 NLRP3 炎症小体信号通路的影响，降低 caspase-1 活性并降低 IL-1¿体外和体内感染 HKx31（一种小鼠适应型流感病毒株）以及原发性和继发性肺炎链球菌（此前已被证明可促进 K+ 外流、增强 IL-1）刺激产生的产物。尽管有这些发现，但由于 ATP 或尼日利亚菌素的化学特性，老年树突状细胞 (DC) 的表达以及 NLRP3 炎性体成分的基因表达增加以及体外流感和肺炎链球菌感染期间 caspase-1 活性增强。使用这些化合物可能会在肺部感染期间对老年宿主产生有害的副作用，因此迫切需要研究其他治疗方法。拟议工作的目标是研究类似于 ATP 或 ATP 的新化合物。尼日利亚菌素有可能刺激老年宿主的 NLRP3 炎症小体激活和救援功能，并改善老年宿主的临床结果。在这一点上，在目标 1 中，我们将检查 NLRP3 炎症小体对可改变氧化应激的药物吡非尼酮的反应功能。，以及寻找可用于增强老年宿主在流感感染期间的 NLRP3 活性的其他化合物（目标 2）。具体来说，我们将采用化学筛选。用于识别 NLRP3 炎性体激活剂的文库，我们将很容易使用体外研究我们将测试以下假设：在流感或肺炎链球菌感染早期对老年宿主进行早期干预，例如刺激 NLRP3 炎性小体，将改善先天免疫反应，从而降低这种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和死亡的主要原因，即使在成人常规疫苗接种的时代，也迫切需要研究新的疗法和治疗策略，以减少严重的后果。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细菌做好准备。完成 R21 中提出的目标将进一步明确 NLRP3 炎性体作为流感和肺炎球菌感染期间重要的先天信号通路的作用。产生的新疗法可以很容易地在原代人类细胞中进行测试，并在其他模型系统中进行评估。