Molecular mechanisms underlying the high mortality of hypervirulent Klebsiella pneumoniae and its effective therapy development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220594 | GEO | 2023/12/26
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC10227003 | biostudies-literature
Project description:To map the Hfq-mediated RNA regulatory network in HvKP, we harnessed the LiRIP-seq approach recently established in our lab, which enabled global profiling of RNA-RNA interactomes in live bacteria. Transformation of the pBAD-t4rnl1 plasmid into Klebsiella allowed us to express T4 RNA ligase 1 for proximity-ligation of RNAs in vivo, followed by co-immunoprecipitation (coIP) to enrich the Hfq-bound RNA transcripts (singleton reads) and ligated RNA fragments (chimeras: sRNA-mRNA, sRNA-sRNA, etc).
2024-07-17 | GSE243246 | GEO
Project description:Purpose:Investigated transcriptome profile changes in the lungs of infected mice at different time points, to increase our understanding of hvKp pulmonary infection and to screen for genes or targets of research value. microarray and quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods and to evaluate protocols for optimal high-throughput data analysis Methods: Animals were randomly divided into four infection groups and one control group (five mice per group), and the infected mice were euthanized at 12, 24, 48 and 60 h post-infection (hpi), respectively, while the control group mice were euthanized immediately after delivery of PBS at the 0 h time point. The lungs of the mice were isolated and divided into two parts for subsequent histopathologic examination or total RNA extraction. Results: Using the control group (0 hpi) as a reference, 6247 DEGs were identified across four time points after hvKp infection. At 12 hpi, 939 upregulated DEGs and 439 downregulated DEGs were detected, and by 60 hpi, 2647 upregulated DEGs and 2806 downregulated DEGs were detected. Overall, the number of upregulated and downregulated DEGs increased over time and a total of 688 genes were upregulated and 240 genes downregulated in common for all time points. And 12 of these were validated with qRT–PCR. RNA-seq data had a linear relationship with qRT–PCR for more than four orders of magnitude and a goodness of fit (R2) of 0.9548. To get a more holistic view, DEGs were clustered into nine clusters according to their temporal expression patterns.WGCNA was performed with the detected DEGs. The dynamic tree cutting algorithm in the WGCNA package was used to process the hierarchical clustering tree, and a total of 28 different modules were finally obtained. Conclusions: Our work both validates the results of previous studies on K. pneumoniae pulmonary infections and provides new additions and insights on hvKp pulmonary infections, which may contribute to the development of therapeutic approaches to reduce hvKp lung inflammation.
2022-03-31 | GSE199546 | GEO
Project description:Hypervirulent Klebsiella pneumoniae (hvKp) is a significant pathogen causing severe community-acquired infections, characterized by the presence of a virulence plasmid. The plasmid-encoded regulator of mucoid phenotype A (RmpA) activates the expression of capsule genes, resulting in a hypermucoviscosity phenotype strongly associated with increased virulence. RmpA features a LuxR DNA-binding domain and a signaling-responsive domain, typical of proteins that regulate multiple biological processes. However, the comprehensive regulatory mechanisms of RmpA in hvKp remain unclear. Herein, RNA-seq showed that RmpA activates carbohydrate metabolism pathways while repressing those related to DNA replication, ribosome metabolism, and biofilm formation. ChIP-seq further confirmed RmpA’s role as a global regulator that not only enhances capsule production by activating transcripts within the capsule locus, but also upregulates the expression of key genes involved in synthesizing capsule precursors. RmpA regulates the phenotypic switch between hypermucoviscosity and biofilm formation by repressing type III fimbriae genes. In addition, Expression of RmpA in Escherichia coli induced global transcriptional changes, suggesting it functions as a global regulator across species. These findings position RmpA as a central regulator in hvKp, orchestrating metabolic pathways and phenotypic traits essential for virulence.
2025-01-14 | GSE286111 | GEO
Project description:Hypervirulent Klebsiella pneumoniae (hvKp) is a significant pathogen causing severe community-acquired infections, characterized by the presence of a virulence plasmid. The plasmid-encoded regulator of mucoid phenotype A (RmpA) activates the expression of capsule genes, resulting in a hypermucoviscosity phenotype strongly associated with increased virulence. RmpA features a LuxR DNA-binding domain and a signaling-responsive domain, typical of proteins that regulate multiple biological processes. However, the comprehensive regulatory mechanisms of RmpA in hvKp remain unclear. Herein, RNA-seq showed that RmpA activates carbohydrate metabolism pathways while repressing those related to DNA replication, ribosome metabolism, and biofilm formation. ChIP-seq further confirmed RmpA’s role as a global regulator that not only enhances capsule production by activating transcripts within the capsule locus, but also upregulates the expression of key genes involved in synthesizing capsule precursors. RmpA regulates the phenotypic switch between hypermucoviscosity and biofilm formation by repressing type III fimbriae genes. In addition, Expression of RmpA in Escherichia coli induced global transcriptional changes, suggesting it functions as a global regulator across species. These findings position RmpA as a central regulator in hvKp, orchestrating metabolic pathways and phenotypic traits essential for virulence.
2025-01-14 | GSE286114 | GEO
Project description:The emergence of hypervirulent Klebsiella pneumoniae (hvKP) strains poses a significant threat to public health due to their high mortality rates and propensity to cause severe community-acquired infections in otherwise healthy individuals. The ability of hvKP to form biofilms and produce a protective capsule contributes to its enhanced virulence and is a significant challenge to effective antibiotic treatment. Therefore, understanding the molecular mechanisms underlying hvKP virulence and biofilm formation is crucial for developing new therapeutic strategies. Polyphosphate Kinase 1 (PPK1) is an enzyme responsible for inorganic polyphosphate synthesis and plays a vital role in regulating various physiological processes in bacteria. In this study, we investigated the impact of polyP metabolism on the biofilm and capsule formation and virulence traits in hvKP using Dictyostelium discoideum amoeba as a model host. We found that the PPK1 null-mutant was impaired in biofilm and capsule formation and showed attenuated virulence in D. discoideum compared to the wild-type strain. We performed a shotgun proteomic analysis of the PPK1 mutant and wild-type strain to gain further insight into the underlying molecular mechanism. The results revealed that the PPK1 mutant had a differential expression of proteins (DEP) involved in capsule synthesis (Wzi - Ugd), biofilm formation (MrkC-D-H), synthesis of the colibactin genotoxin precursor (ClbB), as well as proteins associated with the synthesis and modification of lipid A (ArnB -LpxC - PagP). These proteomic findings corroborate the phenotypic observations and indicate that the PPK1 mutation is associated with impaired biofilm and capsule formation and attenuated virulence in hypervirulent K. pneumoniae. Overall, our study highlights the importance of polyP synthesis in regulating extracellular biomolecules and virulence in K. pneumoniae and provides insights into potential therapeutic targets for treating K. pneumoniae infections.
2024-08-23 | PXD046644 | Pride
Project description:Molecular mechanisms underlying the high mortality of hypervirulent Klebsiella pneumoniae and its effective therapy development
| PRJNA910481 | ENA
Project description:Hypervirulent Klebsiella pneumoniae (HvKP) is an emerging human pathogen causing invasive infection in immune-competent hosts. The hypervirulence is strongly linked to the overproduction of hypermucovisous capsule, but the underlining regulatory mechanism of hypermucoviscosity (HMV) has been elusive, especially at the post-transcriptional level mediated by small RNAs (sRNAs). Using a recently developed RNA interactome profiling approach, we have investigated the Hfq-associated sRNA regulatory network and established the first in vivo RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNA that inhibit or promote HMV. One of the strongest repressors of HMV was ArcZ, a conserved sRNA in the Enterobacteriaceae family. We found that ArcZ is activated by the master regulator of catabolite repression Crp, and down-regulates the expression of mlaA encoding an outer-membrane lipoprotein, leading to decreased HMV and virulence attenuation in mice. ArcZ significantly reduced HMV in several carbapenem-resistant and hypervirulent clinical isolates with diverse genetic background, suggesting it is an antisense RNA inhibitor of HMV with therapeutic potential. In summary, our work provides a comprehensive map of the RNA-RNA interaction network of HvKP and identifies ArcZ as a conserved repressor of HMV, providing novel insights into the mechanisms of posttranscriptional regulations of virulence.
2024-07-17 | GSE260738 | GEO
Project description:Hypervirulent K. pneumoniae (hvKp) is an evolving pathotype that is more virulent than classical K. pneumoniae (cKp). hvKp usually infects individuals from the community, who are often healthy. Infections are more common in the Asian Pacific Rim but are occurring globally. hvKp infection frequently presents at multiple sites or subsequently metastatically spreads, often requiring source control. hvKp has an increased ability to cause central nervous system infection and endophthalmitis, which require rapid recognition and site-specific treatment. The genetic factors that confer hvKp's hypervirulent phenotype are present on a large virulence plasmid and perhaps integrative conjugal elements. Increased capsule production and aerobactin production are established hvKp-specific virulence factors. Similar to cKp, hvKp strains are becoming increasingly resistant to antimicrobials via acquisition of mobile elements carrying resistance determinants, and new hvKp strains emerge when extensively drug-resistant cKp strains acquire hvKp-specific virulence determinants, resulting in nosocomial infection. Presently, clinical laboratories are unable to differentiate cKp from hvKp, but recently, several biomarkers and quantitative siderophore production have been shown to accurately predict hvKp strains, which could lead to the development of a diagnostic test for use by clinical laboratories for optimal patient care and for use in epidemiologic surveillance and research studies.
| S-EPMC6589860 | biostudies-literature
Project description:hvKP ATCC43816 and its lytic phage H5 were employed as a phage-antibiotic combination model. Based on the comprehensive characterization of phages, including cryo-electron microscopy, we evaluated the synergic effect of H5 on bacterial killing in vitro when combined with multiple antibiotics, and analyzed the advantages of phage-antibiotic combinations from an evolutionary perspective and proposes a novel PAS mechanism by using ceftazidime as an example.
2023-09-14 | GSE237490 | GEO