The CpxR response regulator mediates the virulence of <i>Klebsiella pneumoniae</i> by regulating the expression of virulence-associated genes
Bibliographic record
Abstract
ABSTRACT Klebsiella pneumoniae is a prominent human pathogen that has developed resistance to multiple antibiotics. While the roles of capsules and siderophores are well established, the identification of additional virulence determinants remains limited. In this study, we hypothesize that the two-component system response regulator CpxR is integral to the regulation of K. pneumoniae virulence via control of specific virulence-associated genes. The deletion of the cpxR gene resulted in reduced serum resistance and attenuated virulence in both Galleria mellonella larvae and murine infection models compared to the wild-type strain. To elucidate the repertoire of virulence-associated genes regulated by CpxR, a multidisciplinary workflow was employed, integrating RNA sequencing, real-time quantitative PCR, gene knockout strategies, serum resistance assays, and infection experiments utilizing Galleria mellonella . Among the genes identified with significantly diminished expression following cpxR deletion, KPHS_28080 emerged as a novel candidate virulence-associated gene. The deletion of KPHS_28080 impaired serum survival in both the carbapenem-resistant CRKp HS11286 and the hypervirulent hvKp ATCC43816 strains. Furthermore, the deletion of KPHS_28080 in hvKp ATCC43816 led to significantly decreased colonization and impaired dissemination to multiple organs in murine models, corresponding with an overall reduction in virulence. The promoter region of KPHS_28080 harbors a conserved CpxR-binding motif, which enhances promoter activity and gene transcription upon CpxR binding. Sequence alignment revealed that KPHS_28080 encodes a member of the short-chain dehydrogenase family, and this gene is highly conserved among K. pneumoniae strains. These results elucidate the pivotal role of CpxR in mediating virulence in K. pneumoniae and clarify its regulatory impact on virulence-associated gene expression. IMPORTANCE The mechanisms underlying the pathogenicity of Klebsiella pneumoniae , particularly the discovery of novel virulence factor genes, remain poorly understood. CpxR, a response regulator of the two-component system, is critical for mediating envelope stress responses. While CpxR has been implicated in the virulence of diverse bacterial pathogens, its role in K. pneumoniae remains elusive. In this study, we demonstrate that CpxR significantly enhances K. pneumoniae virulence in both Galleria mellonella and murine infection models. Furthermore, we identify a previously uncharacterized virulence-associated gene, encoding a short-chain dehydrogenase/reductase oxidoreductase family member, whose expression is upregulated by CpxR. Given the clinical prevalence and antimicrobial resistance of K. pneumoniae , elucidating CpxR-dependent virulence regulation and its novel target provides a pivotal framework for developing therapeutic strategies against these challenging infections.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".