Deciphering the impact of sedative choice on the dynamics of Klebsiella pneumoniae lung infection

解读镇​​静剂选择对肺炎克雷伯菌肺部感染动态的影响

• 批准号: 10527379
• 负责人: Nancy Elizabeth Freitag
• 金额: $ 19.79万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-16 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527379
• 关键词: Anesthesia procedures; Anesthetics; Animals; Antimicrobial Resistance; Attenuated; Bacteria; COVID-19 pandemic; Cell physiology; Clinical; Colonoscopy; Community-Acquired Infections; Curiosities; Disease; Disease Outcome; Distal; Drug Targeting; Drug usage; Effector Cell; Environment; Gram-Positive Bacterial Infections; Growth; Health Care Costs; Hospitalization; Hospitals; Host resistance; Immune; Immune response; Immune signaling; Immunity; In Vitro; Incidence; Infection; Inpatients; Intravenous; Intubation; Ketamine; Klebsiella pneumoniae; Libraries; Liver; Lung; Lung infections; Maintenance; Mechanical ventilation; Molecular; Nervous System; Nosocomial Infections; Operative Surgical Procedures; Outcome; Outpatients; Pathology; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Population; Predisposition; Procedures; Prognosis; Propofol; Recovery; Reporting; Resistance to infection; Respiratory Disease; Respiratory Tract Infections; Risk; Sedation procedure; Sepsis; Severities; Site; Time; Tissues; Virulence; Virulence Factors; Virulent; Virus Diseases; Xylazine; chemokine; cytokine; design; disease prognosis; experimental study; flexibility; healthcare-associated infections; immunoregulation; in vivo; infection risk; innate immune function; microbial; mouse model; mutant; opportunistic pathogen; pathogen; recruit; sedative; side effect; transposon sequencing

Summary Healthcare-associated infections adversely impact patient outcomes and increase healthcare costs by billions of dollars each year. Anesthetic administration is associated with a significantly increased risk of infection via its alterations of immune signaling and immune effector cell function. Despite the increasing recognition that anesthetics modulate immunity, relatively little remains known regarding the breadth of mechanisms by which drugs that target the nervous system influence host immune responses. We have previously demonstrated that brief sedation with propofol, the most commonly used drug for anesthetic induction, dramatically increases host susceptibility to microbial infection. Propofol is widely used for patients requiring intubation and mechanical ventilation, and patients in the ICU can remain sedated with propofol for days. To better define the impact of propofol sedation on respiratory disease, we have developed a mouse model of lung infection using the Gram- negative opportunistic pathogen Klebsiella pneumoniae (Kp). Kp is a growing threat worldwide as a nosocomial pathogen due to its rapid acquisition of antimicrobial resistance; in addition, hypervirulent strains causing community-acquired infections have been recently reported. Preliminary experiments indicate that propofol sedation dramatically increases the severity of Kp disease pathology within the lungs and promotes bacterial dissemination to distal tissues. Using transposon insertion sequencing (INSeq) and libraries of Kp insertion mutants, we have further demonstrated that the choice of sedative influences the selection of Kp mutants that are defective for growth within the infected lung. These results strongly suggest that propofol not only influences the pathology and outcome of lung infection, but that it also differentially impacts the arsenal of bacterial virulence factors required for disease. This proposal is thus designed to explore two related and mutually important hypotheses, those being (1) that propofol increases host susceptibility to microbial (Kp) infection in the lung via alterations in immune signaling that interfere with the recruitment and function of innate immune effector cells; and (2) the choice of sedation alters the lung environment in ways that impact the Kp global virulence repertoire required for bacterial growth in tissues. Aim 1 experiments will determine how sedation choice influences the outcome and progression of Kp lung infection in vivo. Aim 2 will functionally characterize Kp mutants identified based on their virulence being differentially impacted by sedation with propofol versus ketamine/xylazine. Overall, these experiments will provide valuable and important information regarding the impact of sedation on respiratory infection outcome and prognosis.

概括 与医疗保健相关的感染对患者的结果不利，并增加了数十亿的医疗费用 每年的美元。麻醉药给药与通过 它的免疫信号传导和免疫效应细胞功能的改变。尽管人们越来越认识到 麻醉剂调节免疫力，关于机制的广度，相对较少知道 靶向神经系统的药物会影响宿主免疫反应。我们以前已经证明了 与丙泊酚的简短镇静作用，丙泊酚是最常用的麻醉诱导药物，大大增加了宿主 对微生物感染的敏感性。丙泊酚广泛用于需要插管和机械的患者 通风和ICU中的患者可以用丙泊镇镇静几天。更好地定义 丙泊酚对呼吸道疾病的镇静作用，我们使用革兰氏 肺炎（KP）负性病原体kleblebsiella。 KP是全球越来越多的威胁 由于迅速获得抗菌素耐药性，医院病原体；另外，高毒性菌株 最近报道了引起社区获得的感染。初步实验表明 丙泊酚镇静剂大大增加了肺部KP疾病病理的严重程度，并促进 细菌传播到远端组织。使用转座子插入测序（inseq）和KP的库 插入突变体，我们进一步证明了镇静剂的选择会影响KP的选择 感染肺内生长有缺陷的突变体。这些结果强烈表明丙泊酚不是 仅影响肺部感染的病理和结果，但它也会差异地影响 疾病所需的细菌毒力因子。因此，该建议旨在探索两个相关的 相互重要的假设，丙泊酚增加宿主对微生物（KP）的敏感性的假设（1） 通过改变免疫信号传导的肺部感染，干扰了先天的募集和功能 免疫效应细胞； （2）镇静的选择以影响KP的方式改变了肺部环境 组织中细菌生长所需的全球毒力库。 AIM 1实验将确定如何 镇静选择会影响体内KP肺部感染的结果和进展。 AIM 2将在功能上 根据KP突变体的毒力被镇静而被镇静作用的特征 丙泊酚与氯胺酮/甲基嗪。总体而言，这些实验将提供宝贵而重要的信息 关于镇静对呼吸道感染结果和预后的影响。