Deciphering how anesthetics increase host susceptibility to microbial infection

描述(由申请人提供)：麻醉管理与医院手术患者感染风险的显著增加有关。虽然有几项研究报道了常用麻醉药与免疫细胞功能下降之间的联系，但目前对靶向神经系统的药物影响宿主免疫反应的分子机制知之甚少。对神经系统和免疫系统之间沟通途径的更好理解将澄清特定的麻醉药如何使个人面临更大的微生物感染风险。单核细胞增生性李斯特菌(Listeria monuctogen，Lm)几十年来一直是破译宿主对微生物感染反应的一个强大的模式系统，并且一直是阐明先天免疫和获得性免疫新模式的工具。在已建立的小鼠LM感染模型的基础上，本提案中概述的实验将使用LM来阐明常用的外科麻醉剂，如异丙酚，显著增加宿主对微生物感染的敏感性的机制。初步数据显示，与不接受药物治疗的小鼠相比，在感染LM之前静脉注射麻醉剂的小鼠，靶器官中的细菌负荷增加了1万多倍。异丙酚是人类手术中最常用的麻醉剂，被发现可以减少细菌从小鼠靶器官中的清除，并改变宿主的先天性免疫信号。这一建议的工作假设是，异丙酚和其他麻醉剂通过促进细菌跨宿主屏障的移位，同时也阻止先天免疫效应细胞招募到细菌感染部位，增加了宿主对微生物感染的易感性。目标1中的实验将检查麻醉暴露对宿主免疫的多个方面的影响，包括细胞因子和趋化因子信号以及单核细胞在细菌感染部位的募集。目的2实验将确定异丙酚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，特别是在宿主内占据不同细胞内和细胞外复制生态位的细菌。这些试点研究的结果将是对麻醉剂如何抑制宿主免疫的更深入了解，产生的数据将成为未来合作项目的基础，这些合作项目旨在破译连接中枢神经系统和宿主免疫功能的途径。这一新的研究领域有可能通过认识到麻醉暴露对宿主免疫反应的负面影响以及认识到麻醉增加宿主易感性的感染类型，最终降低手术后感染的频率和严重程度。

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.