David Clement, Czauderna Aleksander, Cheng Liqing, Lagune Marion, Jung Hea-Jin, Kim Sohn G, Pamer Eric G, Prados Julien, Chen Liang, Becattini Simone
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Gut Microbes. 2024 Jan-Dec;16(1):2340486. doi: 10.1080/19490976.2024.2340486. Epub 2024 Apr 24.
Carbapenem-resistant (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 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 i 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, 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.
耐碳青霉烯类（CR-Kp）对全球公共卫生构成重大威胁。CR-Kp的主要储存库是肠道。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大量繁殖，主要发生在医院环境中。肠道环境紊乱对这种病原体的适应性、生存、扩张和药敏性的影响尚未得到充分了解，但设计应对CR-Kp定植和感染的策略可能与之相关。在这里，我们采用了一种模型来研究CR-Kp临床分离株对肠道免疫激活的转录适应性。我们报告，早在宿主用抗CD3抗体治疗6小时后，CR-Kp就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、抗生素抗性和应激反应的基因上调。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，然而它们的缺失并不损害免疫激活时CR-Kp的适应性。转录因子富集分析确定全局调节因子环磷酸腺苷受体蛋白（CRP）是观察到的转录特征的潜在协调者。与CRP在调节替代碳源利用中的公认作用一致，CR-Kp中的CRP缺失导致肠道定植严重受损，尽管这种效应未因免疫激活而放大。因此，在以CRP依赖方式发生肠道定植后，CR-Kp可以通过实施一个明确且复杂的转录程序快速响应免疫信号，该程序与细菌适应性的直接相关性值得进一步研究。利用该模型的其他分析可能会确定应对CR-Kp肠道定植的关键因素。
