Deciphering how anesthetics increase host susceptibility to microbial infection

描述（由申请人提供）：麻醉给药与医院手术患者感染风险显著增加有关。虽然有几项研究报道了常用麻醉剂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交流途径的进一步了解将阐明特定麻醉剂如何使个体面临更大的微生物感染风险。几十年来，兼性单核增生李斯特菌（Listeria monocytogenes, Lm）一直是一种强大的模型系统，用于破译宿主对微生物感染的反应，并且该生物继续作为阐明先天免疫和适应性免疫新范式的工具。基于已建立的小鼠Lm感染模型，本提案中概述的实验将利用Lm来阐明常用手术麻醉剂（如异丙酚）显着增加宿主对微生物感染易感性的机制。初步数据表明，与未接受药物治疗的小鼠相比，在感染Lm之前给小鼠静脉注射麻醉剂会使靶器官的细菌负担增加1万多倍。异丙酚是人类手术中最常用的麻醉剂，它被发现可以减少小鼠靶器官对细菌的清除，并改变宿主的先天免疫信号。该建议的工作假设是，异丙酚和可能的其他麻醉剂通过增强细菌跨宿主屏障的易位而增加宿主对微生物感染的易感性，同时也阻碍先天免疫效应细胞向细菌感染部位的招募。Aim 1的实验将检查麻醉暴露对宿主对Lm感染免疫的多个方面的影响，包括细胞因子和趋化因子信号传导以及单核细胞向细菌感染部位的募集。目的2实验将确定丙泊酚暴露是否对增加宿主对其他微生物病原体的敏感性有广泛的影响，特别是在宿主体内占据不同细胞内和细胞外复制生态位的细菌。这些初步研究的结果将是更深入地了解麻醉剂如何抑制宿主免疫，所产生的数据将构成未来合作项目的基础，旨在破译中枢神经系统与宿主免疫功能之间的联系。这一新的研究领域有可能通过识别受麻醉暴露负面影响的宿主免疫反应，以及识别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.