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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.
Acknowledgments
We thank Diego Andrey, Roberto Sierra-Miranda, Melanie Roch, William Kelley and Wolf-Dietrich Hardt for constructive discussion. Also, I would need to add the following at the end:Sequencing experiments were performed at the iGE3 Genomics Platform of the University of Geneva (https://ige3.genomics.unige.ch). Figures depicting experimental layouts were created with BioRender.com.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings reported in this study are openly available on Yareta [DOI: 10.26037/yareta:qbe6nnbwlbg2ne7ob43cbdkklq].
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2340486