Deciphering how anesthetics increase host susceptibility to microbial infection

破译麻醉剂如何增加宿主对微生物感染的易感性

基本信息

批准号：
8462202
负责人：
Nancy Elizabeth Freitag
金额：
$ 7.3万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462202
关键词：
Anesthesia procedures Anesthetics Animals Area Bacteria Bacterial Infections Bacterial Model Bacterial Translocation Biological Models Cell physiology Cells Communication Data Development Drug Targeting Effector Cell Foundations Frequencies Future Health Hospital Costs Hospitals Host resistance Human Immune Immune response Immune system Immunity In Vitro Individual Infection Ketamine Link Listeria monocytogenes Modeling Molecular Mus Natural Immunity Nervous system structure Neuraxis Nosocomial Infections Operative Surgical Procedures Organ Organism Outcome Pathway interactions Patients Pentobarbital Pharmaceutical Preparations Pilot Projects Population Predisposition Production Propofol Reporting Research Resistance to infection Risk Salmonella typhimurium Serum Severities Signal Transduction Site Streptococcus pyogenes Superoxides Tissues Work adaptive immunity base cell mediated immune response chemokine cytokine design extracellular immune clearance immune function improved intravenous administration macrophage microbial monocyte mouse model novel pathogen research study tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Anesthetic administration is associated with a significantly increased risk of infection in hospital patients undergoing surgery. While several studies have reported linkages between commonly used anesthetics and decreased immune cell function, little is currently known regarding the molecular mechanisms by which drugs that target the nervous system influence host immune responses. An improved understanding of pathways of communication between the nervous and immune systems would clarify how specific anesthetics place individuals at greater risk for microbial infection. The facultative intracellular bacterial pathogen Listeria monocytogenes (Lm) has served for decades as a powerful model system for deciphering host responses to microbial infection, and the organism continues to serve as tool for elucidating new paradigms of innate and adaptive immunity. Based on the well-established mouse model of Lm infection, experiments outlined within this proposal will use Lm to elucidate the mechanisms by which commonly used surgical anesthetics, such as propofol, dramatically increase host susceptibility to microbial infection. Preliminary data indicates that intravenous administration of anesthetics to mice prior to Lm infection increased bacterial burdens in target organs by more than 10,000-fold in comparison to none drug-treated animals. Propofol, the most commonly used anesthetic in human surgeries, was found to reduce the clearance of bacteria from mouse target organs and to alter host innate immune signaling. The working hypothesis of this proposal is that propofol and possibly other anesthetic agents increase host susceptibility to microbial infection by enhancing bacterial translocation across host barriers while also impeding the recruitment of innate immune effector cells to sites of bacterial infection. Experiments in Aim 1 will examine the impact of anesthetic exposure on multiple facets of host immunity to Lm infection, including cytokine and chemokine signaling and monocyte recruitment to sites of bacterial infection. Aim 2 experiments will determine if propofol exposure has broad effects towards increasing host susceptibility to other microbial pathogens, specifically bacteria that occupy different intracellular and extracellular replication niches within the host. The outcome of these pilot studies will be a deeper understanding of how anesthetic agents suppress host immunity, and the data generated will form the basis for future collaborative projects designed to decipher the pathways that link the central nervous system with host immune function. This novel area of research has the potential to ultimately reduce the frequency and severity of post-surgical infections via the recognition of host immune responses negatively impacted by anesthetic exposure and by recognition of the types of infections for which anesthesia increases host susceptibility.

描述（由申请人提供）：麻醉剂与接受手术的医院患者的感染风险显着增加有关。虽然几项研究报告了通常使用麻醉药和免疫细胞功能降低之间的联系，但目前，关于靶向神经系统的药物会影响宿主免疫反应的分子机制，目前几乎不知所知。对神经和免疫系统之间交流途径的提高理解将阐明特定麻醉剂如何使个人面临微生物感染的风险更大。辅助细胞细菌病原体单核细胞增生李斯特菌（LM）已成为一种强大的模型系统，用于破译宿主对微生物感染的反应，并且该有机体继续用作阐明新的先天和适应性免疫的新范式的工具。基于公认的LM感染小鼠模型，该提案中概述的实验将使用LM来阐明通常使用的手术麻醉药（例如丙泊酚）的机制，例如丙泊酚，大大提高了宿主对微生物感染的易感性。初步数据表明，与没有药物治疗的动物相比，在LM感染之前静脉内给予小鼠麻醉药增加了靶器官的细菌负担超过10,000倍。丙泊酚是人类手术中最常用的麻醉剂，可降低小鼠靶器官细菌的清除，并改变宿主先天免疫信号传导。该提议的工作假设是，丙泊酚和可能其他麻醉剂通过增强宿主屏障的细菌易位，同时也阻碍了先天免疫效应细胞对细菌感染部位的募集，从而增加了宿主对微生物感染的易感性。 AIM 1中的实验将检查麻醉暴露对宿主免疫对LM感染的多个方面的影响，包括细胞因子和趋化因子信号传导和单核细胞募集对细菌感染部位的影响。 AIM 2实验将确定丙泊屈暴露是否对增加宿主对其他微生物病原体的易感性有广泛的影响，特别是占主体内细胞内和细胞外复制壁c的细菌。这些试验研究的结果将更深入地了解麻醉药物如何抑制宿主的免疫力，而生成的数据将成为未来的协作项目的基础，该项目旨在破译将中枢神经系统与宿主免疫功能联系起来的途径。这一新的研究领域有可能通过识别宿主免疫反应的频率和严重程度，并通过麻醉暴露对宿主免疫反应产生负面影响，并通过识别麻醉增加宿主易感性的感染类型。