PDF(Pubmed)
Abstract：
Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is a significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract. There, the bacterium is usually present at low density but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood, yet it may be relevant to devise strategies to tackle CR-Kp colonization and infection. Here, we adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, treatment increased the concentration of oxidative species and amino acids in the mouse intestine. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were strongly upregulated, however their deletion did not impair CR-Kp fitness in vivo upon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein, CRP, as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, crp deletion in CR-Kp resulted in strongly impaired gut colonization, although this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance toward bacterial fitness warrants further investigation. Additional analyses utilizing this model may identify key factors to tackle CR-Kp colonization of the intestine.
摘要：
耐碳青霉烯类肺炎克雷伯菌（CR-Kp）是全球公共卫生的重大威胁。CR-Kp的主要储库是肠道。在那里,这种细菌通常以低密度存在，但在抗生素治疗后可能会开花，主要是在医院设置。肠道环境紊乱对健康的影响，生存,扩展,对这种病原体的药物敏感性还没有得到很好的理解，然而，这可能与制定应对CR-Kp定植和感染的策略有关。这里,我们采用体内模型来检测CR-Kp临床分离株对肠道免疫激活的转录适应性.我们报告说，早在宿主用抗CD3抗体治疗后6小时，CR-Kp经历了快速的转录变化，包括参与糖利用和氨基酸生物合成的基因下调，以及参与氨基酸摄取和分解代谢的基因上调。抗生素耐药性,和应激反应。与这些发现一致，治疗增加了小鼠肠道中氧化物质和氨基酸的浓度。编码含有未知功能结构域（DUF）1471的蛋白质的基因被强烈上调，然而,它们的缺失在免疫激活后不会损害CR-Kp在体内的适应性.转录因子富集分析确定了全局调节因子cAMP-受体蛋白，CRP,作为观察到的转录签名的潜在协调器。为了与公认的CRP在调节替代碳源利用中的作用保持一致，CR-Kp中的crp缺失导致强烈受损的肠道定植，尽管这种作用没有被免疫激活放大。因此，肠道定植后，以依赖CRP的方式发生，CR-Kp可以通过实施明确定义且复杂的转录程序来快速响应免疫提示，该转录程序与细菌适应性直接相关，值得进一步研究。利用该模型的其他分析可以确定解决肠道CR-Kp定植的关键因素。
