Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

BackgroundLinezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown. MethodsA lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1β, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses. ResultsLZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1β, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy. ConclusionLZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.

背景：利奈唑胺（Linezolid, LZD）对耐甲氧西林金黄色葡萄球菌（Methicillin-resistant Staphylococcus aureus, MRSA）肺炎患者具有临床获益，但在MRSA介导的肺炎病程中，LZD是否以及如何在mRNA水平调控宿主肺部的全局免疫应答，目前尚不明确。
方法：本研究采用USA300菌株介导的致死性MRSA肺炎小鼠模型，探究LZD对小鼠生存率的影响；同时构建亚致死剂量感染的小鼠模型，考察LZD对MRSA肺炎进程中细菌清除能力及肺部基因表达的作用。对C57Bl6小鼠每日腹腔注射100mg/kg的LZD，连续给药3天。于感染后第1天和第3天，检测支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）的蛋白浓度，以及IL6、TNFα、IL1β、干扰素-γ（Interferon-γ）和IL17等细胞因子的水平。在亚致死感染模型中，取左侧肺组织检测细菌清除率，右侧肺组织用于肺部免疫应答的全基因组转录组分析。
结果：LZD治疗可显著提升小鼠生存率并增强细菌清除能力；同时显著降低BALF蛋白浓度及IL6、IL1β、干扰素-γ、IL17等细胞因子的水平。但LZD给药未引发小鼠肺部出现显著的基因表达变化。
结论：LZD对MRSA肺炎具有治疗获益，但并不会在转录水平调控宿主肺部的免疫应答。