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

总结 医疗保健相关感染对患者结局产生不利影响，并增加数十亿美元的医疗保健成本 美元，每年。麻醉剂给药与感染风险显著增加相关， 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， 尽管麻醉剂调节免疫力，但关于麻醉剂调节免疫力的机制的广度仍知之甚少。 靶向神经系统的药物会影响宿主的免疫反应。我们之前已经证明， 最常用的麻醉诱导药物异丙酚的短暂镇静， 易受微生物感染。丙泊酚广泛用于需要插管和机械通气的患者。 ICU的病人可以用异丙酚镇静几天。为了更好地定义 异丙酚镇静呼吸系统疾病，我们已经建立了一个小鼠肺部感染模型，使用革兰氏阴性杆菌， 阴性条件致病菌肺炎克雷伯菌（Kp）。Kp是一个日益增长的威胁， 医院病原体由于其快速获得抗菌药物耐药性;此外， 引起社区获得性感染的病例最近已有报道。初步实验表明， 丙泊酚镇静显著增加肺内Kp疾病病理的严重性， 细菌播散至远端组织。使用转座子插入测序（INSeq）和Kp文库 插入突变体，我们进一步证明了镇静剂的选择影响Kp的选择， 在受感染的肺内生长有缺陷的突变体。这些结果有力地表明，丙泊酚 它不仅影响肺部感染的病理和结果，而且还不同程度地影响 致病所需的细菌毒力因子。因此，本建议旨在探讨两个相关的， 相互重要的假设，这些假设是（1）丙泊酚增加宿主对微生物的敏感性（Kp） 通过免疫信号传导的改变，干扰先天免疫应答的募集和功能， 免疫效应细胞;和（2）镇静剂的选择改变肺环境的方式，影响Kp 组织中细菌生长所需的全球毒力库。目标1实验将确定如何 镇静剂的选择影响体内Kp肺部感染的结果和进展。目标2将在功能上 表征Kp突变体，基于它们的毒力被镇静作用不同地影响， 异丙酚与氯胺酮/甲苯噻嗪。总的来说，这些实验将提供有价值的重要信息 关于镇静对呼吸道感染结果和预后的影响。

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.