Intestinal carbapenem-resistant Klebsiella pneumoniae undergoes complex transcriptional reprogramming following immune activation


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, the authors adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. They 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.

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Why is this important?

Multidrug-resistant (MDR) bacterial infections pose a serious threat to global health, with antibiotic-resistant Klebsiella pneumoniae (Kp) among the top concerns. A recent analysis linked Kp to approximately 600,000 deaths in 2019, with nearly half attributable to antibiotic resistance. Antibiotic-resistant Kp (MDR Kb) thrives in the intestinal tract, especially after antibiotic use in healthcare settings, leading to infections and transmission to other patients. Although mouse models have shed light on Kp colonisation, understanding of its interaction with host immunity remains limited. By studying a model of acute immune response in mice, the authors of this article observed significant changes in gene expression of MDR Kp, suggesting rapid adaptation to immune signals by reconnecting metabolic pathways. With this model, the authors identified multiple genes of potential therapeutic relevance aimed at decreasing the density of Klebsiella pneumoniae in the gut of patients.


29 Apr 2024