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

此修订后的竞争性更新申请是根据NIH多重PI倡议提交的 (http http：//grants.nih.gov/grants/guide/code-files/NOT-OD-11-118.html）。艾德舍伍德和大卫威廉姆斯医生 将担任私家侦探多PI策略是有利的，因为它使“团队科学”的方法 这将平等地利用双方的专业知识和经验，他们的研究小组和他们的 各自的机构。重症患者经常会出现复杂的疾病谱， 包括急性呼吸窘迫综合征、全身炎症反应综合征、脓毒症综合征 脓毒性休克和/或多器官功能障碍综合征。在美国，约951，000例患者/年发生 这些患者中约有一半在ICU中，总体死亡率为28.6%。那些 在最初的败血症事件中存活下来的患者可能最终死于广泛的器官功能障碍， 可以是急性的，由于高度炎症反应，或由于免疫功能障碍而更长时间。公 接受脓毒症导致免疫系统抑制，脓毒症诱导的免疫麻痹 使重症患者易于继发感染。尝试开发有效的治疗方法， 预防或治疗脓毒症及其相关的免疫抑制已被证明是极其困难的。事实上，我认为， 目前FDA还没有批准用于治疗脓毒症的药物。最近的数据显示， 令人信服的证据表明，先天免疫系统可以“训练”，以更迅速，更有效地应对 病原体在该修改的申请中，我们提出了新颖的概念，即可以“训练” 受损的免疫系统，使得可以对现有的和/或随后的免疫系统产生有效的应答。 感染.我们假设“先天免疫训练将重新编程代谢，转录， 败血症患者单核细胞和巨噬细胞的表观基因组和功能表型， 赋予增强的抗感染性”。为了批判性地评估这一假设，我们提出以下建议 具体目标。目标1。确定β-葡聚糖诱导的代谢重编程的功能作用， 在人单核细胞和巨噬细胞中诱导和维持训练的免疫力。为此，我们会 探索诱导训练表型所必需的细胞和分子机制。 具体而言，我们将研究训练的人单核细胞/巨噬细胞的代谢表型， 确定代谢重编程的功能重要性，以诱导和维持训练有素的 白细胞中的表型。目标二。阐明成人先天免疫训练的机制， 年龄的函数。在这个目标中，我们将研究免疫训练对白细胞老化的影响。 人类在离体实验中，我们将检查细胞因子分泌、代谢重编程、基因重组、基因表达、细胞周期和细胞周期。 表达、表观基因组、线粒体功能和人单核细胞的抗微生物功能， 巨噬细胞对免疫训练的反应。目标3。检查白细胞免疫训练的效果 分离自败血症患者。在这个目标中，我们将使用来自人的单核细胞或单核细胞衍生的巨噬细胞。 败血症患者我们将研究免疫训练对代谢重编程，基因表达， 败血症患者单核细胞和巨噬细胞表观基因组、线粒体活性和功能 患者这项研究的成功完成将提供丰富的新的和新颖的信息， 在存在和不存在脓毒症的情况下驱动训练免疫的机制。更重要的是，这 研究将调查先天免疫训练作为预防和/或改善脓毒症的策略， 重症患者的败血症后遗症。

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.