Training Innate Immunity: A new approach to the treatment of Sepsis

训练先天免疫：治疗脓毒症的新方法

• 批准号: 10669060
• 负责人: EDWARD R SHERWOOD
• 金额: $ 52.67万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669060
• 关键词: Acetyl Coenzyme A; Acute; Acute Respiratory Distress Syndrome; Address; Adult; Age; Age Years; Aging; Automobile Driving; Cause of Death; Citrates; Citric Acid Cycle; Complex; Cost of Illness; Critical Illness; Data; Disease; Elderly; Event; Expenditure; FDA approved; Failure; Functional disorder; Gene Expression; Generations; Grant; Hospitals; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Memory; Immunosuppression; Incidence; Individual; Infection; Inflammatory Response; Innate Immune System; Institution; Intensive Care Units; Leukocytes; Macrophage; Maintenance; Metabolic; Mitochondria; Modeling; Molecular; Multiple Organ Failure; Natural Immunity; Organ; Outcome; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Production; Reporting; Research; Resistance to infection; Respiratory Burst; Respiratory distress; Role; Science; Secondary to; Sepsis; Sepsis Syndrome; Septic Shock; Severities; Shock; Signal Transduction; Syndrome; Systemic Inflammatory Response Syndrome; Time; Training; Training Support; United States; United States National Institutes of Health; aged; antimicrobial; beta-Glucans; clinically relevant; cognitive disability; comorbidity; cytokine; effective therapy; epigenome; epigenomics; experience; experimental study; hospital readmission; human disease; human old age (65+); immune function; improved; in vivo; in vivo Model; innate immune mechanisms; metabolic phenotype; monocyte; mortality; novel; novel strategies; pathogen; physically handicapped; prevent; programs; recurrent infection; response; secondary infection; septic; septic patients; systemic inflammatory response; transcriptomics

This revised competitive renewal application is submitted under the NIH multiple PI initiative (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html). Drs. Ed Sherwood and David Williams will serve as the PIs. The multiple PI strategy is advantageous because it enables a “team science” approach that will draw equally on the expertise and experience of both of the PIs, their research groups and their respective institutions. The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome, septic shock and/or multiple organ dysfunction syndrome. In the United States ~951,000 patients/year develop sepsis with approximately half of these patients in the ICU and an overall mortality rate is 28.6%. Those patients that survive the initial septic event may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due to immune dysfunction. It is well accepted that sepsis causes suppression of the immune system and that sepsis-induced immunoparalysis predisposes the critically ill patient to secondary infections. Attempts at developing effective therapies to prevent or treat sepsis and its associated immunosuppression have proven to be exceedingly difficult. In fact, no drugs are currently approved by the FDA for the management of sepsis. Recent data have provided compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to pathogens. In this revised application, we propose the novel concept that it may be possible to “train” the compromised immune system, such that an effective response can be mounted to existing and/or subsequent infections. We hypothesize that “innate immune training will reprogram the metabolic, transcriptomic, epigenomic and functional phenotype of monocytes and macrophages from patients with sepsis and confer augmented resistance to infection”. To critically evaluate this hypothesis, we propose the following specific aims. Aim 1. Define the functional role of β-glucan-induced metabolic reprogramming for inducing and sustaining trained immunity in human monocytes and macrophages. In this aim, we will explore the cellular and molecular mechanisms that are essential for induction of the trained phenotype. Specifically, we will investigate the metabolic phenotype of trained human monocyte/macrophages and determine the functional importance of metabolic reprogramming for inducing and sustaining the trained phenotype in leukocytes. Aim 2. Elucidate the mechanisms of innate immune training in human adults as a function of age. In this aim, we will examine the impact of immune training on leukocytes from aging humans. In ex vivo experiments, we will examine cytokine secretion, metabolic reprogramming, gene expression, the epigenome, mitochondrial function and the anti-microbial functions of human monocytes and macrophages in response to immune training. Aim 3. Examine the effect of immune training in leukocytes isolated from sepsis patients. In this aim, we will employ monocytes or monocyte derived macrophages from sepsis patients. We will examine the effect of immune training on metabolic reprogramming, gene expression, the epigenome, mitochondrial activity and functionality of human monocytes and macrophages from septic patients. Successful completion of this research will provide a wealth of new and novel information on the mechanisms driving trained immunity in the presence and absence of sepsis. Of greater significance, this research will investigate innate immune training as a strategy for preventing and/or ameliorating sepsis and septic sequelae in the critically ill patient.

该修订后的竞争更新申请根据NIH多重PI启动提交 （http://grants.nih.gov/grants/guide/notice-files/not-od-11-118.html）。博士。埃德·舍伍德（Ed Sherwood）和大卫·威廉姆斯（David Williams） 将用作PI。多重PI策略是有利的，因为它可以采用“团队科学”方法 这将同等地借鉴PI，他们的研究小组及其两个PI的专业知识和经验 重症患者经常会发展出复杂的疾病频谱 包括急性呼吸窘迫综合征，全身性炎症反应综合征，脓毒症综合征， 化脓性休克和/或多个器官功能障碍综合征。在美国，大约951,000名患者/年开发 ICU中这些患者中约有一半的败血症和总死亡率为28.6％。那些 在初始化粪池事件中生存的患者最终可能会屈服于宽度的器官功能障碍，可以 由于过度炎症反应，要么是急性，要么由于免疫功能障碍而延长。很好 接受败血症会导致免疫系统抑制，并败血症诱导的免疫分析 使重症患者易患继发性感染。尝试开发有效疗法的尝试 预防或治疗败血症及其相关的免疫抑制已被证明非常困难。实际上， FDA目前尚无药物用于败血症的管理。最近的数据提供了 令人信服的证据表明，可以对先天免疫系统进行“训练”以更快，更有效地做出反应 病原体。在此修订的应用中，我们提出了一个新颖的概念，即可能可以“训练” 免疫系统受损，以便可以安装有效的响应，以对现有和/或随后的响应 感染。我们假设“先天免疫训练将重新编程代谢，转录组， 败血症患者的单核细胞和巨噬细胞的表观基因组和功能表型 赋予对感染的增强抵抗力”。为了批判性评估这一假设，我们提出以下 具体目标。 AIM 1。定义β-葡聚糖诱导的代谢重编程的功能作用 在人类单核细胞和巨噬细胞中诱导和维持受过训练的免疫力。在这个目标中，我们将 探索对于诱导训练的表型必不可少的细胞和分子机制。 具体而言，我们将研究受过训练的人类单核细胞/巨噬细胞的代谢表型和 确定代谢重编程在诱导和维持训练的功能重要性 白细胞中的表型。目标2。阐明人类成年人先天免疫训练的机制 年龄的功能。在此目标中，我们将研究免疫训练对衰老的白细胞的影响 人类。在离体实验中，我们将检查细胞因子分泌，代谢重编程，基因 表达人类单核细胞的表达，线粒体功能和抗微生物功能 巨噬细胞响应免疫训练。目标3。检查白细胞中免疫训练的效果 从败血症患者中分离出来。在此目标中，我们将采用单核细胞或单核细胞衍生的巨噬细胞 败血症患者。我们将检查免疫训练对代谢重编程，基因表达的影响， 脓毒症的人类单核细胞和巨噬细胞的表观基因组，线粒体活性和功能 患者。这项研究的成功完成将提供大量有关的新信息 在存在和不存在败血症的情况下，驱动训练有素的免疫力的机制。更大的意义，这 研究将调查先天免疫训练，作为预防和/或改善败血症和/或 生病患者的化粪池后遗症。