Evaluating the Role of Neutrophils in the Progression of Pneumonic Plague

评估中性粒细胞在肺鼠疫进展中的作用

• 批准号: 9412118
• 负责人: WILLIAM E GOLDMAN
• 金额: $ 18.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-11 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412118
• 关键词: Animal Model; Antibiotic Therapy; Antibiotics; Apoptosis; Bacteria; Classification; Coupled; Cytokine Activation; Data; Disease; Disease Outcome; Disease Progression; Elements; Evaluation; Hour; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Integration Host Factors; Interleukin-1 Receptors; Interleukin-1 beta; Kinetics; Knockout Mice; Laboratories; Lesion; Lung; Lung Inflammation; Lung infections; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Neutrophil Infiltration; Organism; Pathogenesis; Phase; Play; Pneumonia; Pneumonic Plague; Process; Production; Proteins; Pulmonary Inflammation; Pulmonary Pathology; Regulation; Reporting; Role; Severities; Severity of illness; Site; Symptoms; Testing; Therapeutic; Virulent; Work; Yersinia pestis; anakinra; cytokine; experimental study; inhibitor/antagonist; innate immune function; insight; lung injury; mortality; mouse model; neutrophil; optimal treatments; pathogen; respiratory; theories

Summary Abstract Pneumonic plague is the deadliest form of disease caused by Yersinia pestis and the basis for its classification as a Tier 1 Select Agent. In the absence of antibiotics, mortality rates approach 100% within a week of inhalation of Y. pestis. The progression of pneumonic plague begins with an extended “pre-inflammatory” phase, featuring no disease symptoms despite a rapidly increasing number of bacteria in the lung. After 36-48 hours, there is an abrupt switch to a “pro-inflammatory” phase characterized by the rapid onset of symptoms, the induction of pro-inflammatory cytokines, and the dramatic accumulation of neutrophils in the airways. Progression into the pro-inflammatory phase of disease leads to the severe necrotizing pneumonia that is the hallmark of pneumonic plague, but the factors influencing this biphasic disease progression are poorly defined. The objective of the work proposed here is to characterize the pulmonary factors/conditions that control the onset of inflammation and the neutrophil-related processes that contribute to host damage. The first Aim probes the regulation of inflammation during the pre-inflammatory phase. We have previously shown that virulent Y. pestis triggers early production of a pro-inflammatory cytokine (IL-1β) in the lung, and we have preliminary data suggesting that this is due to simultaneous induction of the IL-1 receptor antagonist (IL-1RA). We will test that theory by selective addition/depletion experiments, coupled with evaluation of the kinetics of neutrophil influx and other parameters of disease progression. The second Aim focuses on neutrophil-mediated damage in the pro-inflammatory phase. We recently reported that depletion of neutrophils prior to pulmonary infection with Y. pestis significantly diminishes inflammatory lung pathology. We will utilize currently available knockout mouse lines to implicate neutrophil-related functions that contribute to the inflammatory damage in the lung. Furthermore, we will use commercially available inhibitors to suppress host innate immune functions and enhance antibiotic efficacy for treating pneumonic plague.

摘要摘要 肺鼠疫是由鼠疫耶尔森氏菌引起的最致命的疾病，也是其分类的基础 作为第1级选择代理。在没有抗生素的情况下，一周内死亡率接近100% 吸入鼠疫杆菌。肺鼠疫的进展始于长期的“炎症前状态”。 阶段，没有疾病症状，尽管肺部细菌数量迅速增加。之后 36-48小时，突然切换到“促炎”阶段，其特征是迅速发作 症状，促炎细胞因子的诱导，以及中性粒细胞的戏剧性积累 航空公司。进入疾病的促炎阶段会导致严重的坏死性肺炎 这是肺鼠疫的特征，但影响这种双相疾病进展的因素是 定义不明确。在这里提出的工作的目的是描述肺部因素/条件的特征 控制炎症的发生和与中性粒细胞相关的有助于宿主的过程 损坏。 第一个目的是探讨炎症前阶段的炎症调节。我们有 此前研究表明，强毒鼠疫杆菌可在体内早期产生促炎细胞因子(IL-1β) 肺，我们有初步数据表明这是由于同时诱导IL-1 受体拮抗剂(IL-1RA)。我们将通过选择性添加/耗尽实验来验证这一理论， 再加上中性粒细胞流入的动力学和疾病进展的其他参数的评估。 第二个目标集中在中性粒细胞介导的促炎阶段的损伤。我们最近 报告说，在肺部感染鼠疫杆菌之前，中性粒细胞的耗尽显著减少 炎性肺病理。我们将利用目前可用的基因敲除鼠系来牵连 导致肺部炎症损伤的中性粒细胞相关功能。此外，我们还将 使用商业上可获得的抑制剂来抑制宿主的先天免疫功能并增强抗生素 治疗肺鼠疫的疗效。