Chongfan Technology
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26
2024
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08
China Agricultural University Wang Yang/Wu Congming/Shen Jianzhong and other cooperation latest PNAS
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The emergence of carbapenem-resistant, highly pathogenic Klebsiella pneumoniae (CR-hvKp) is a growing problem due to its high mortality rate and limited treatment options. While high viscosity is critical for CR-hvKp infection, the role of bacterial viscosity changes in CR-hvKp host colonization and persistence is not well defined.
On August 16, 2024, China Agricultural University Wang Yang, Wu Congming, Shen Jianzhong and Fudan University Hu Fupin jointly communicatedPNAS (IF = 9.4) published online entitled"Adaptive evolution of carbapenem-resistant hypervilulent Klebsiella pneumoniae in the urinary tract of a single patient"The research paper.The study observed a phenotypic switch from high to low viscosity in CR-hvKp in a patient with a scrotal abscess and a urinary tract infection (UTI).
This switch is attributed to the decreased expression of rmpADC (mucus phenotype regulator), which is caused by the deletion of the upstream insertion sequence ISKpn26. After conversion, the low-viscosity variant had a 9.0-fold reduction in mortality in mice with sepsis, a more than 170.0-fold reduction in the ability to evade macrophage phagocytosis in vitro, and a 11.2-to 40.9-fold reduction in growth rate in normal mouse serum. In contrast, the residence time of the low-viscosity variant in the mouse urinary tract was increased (21 days vs. 6 days), the adhesion to bladder epithelial cells was increased by 216.4 times, and the biofilm production was enhanced by 48.7. Notably, the CR-hvKp viscosity shift was reproduced in a mouse model of urinary tract infection without antibiotics. The in vivo generation of low-viscosity variants is mainly associated with defective or low expression of rmpADC or capsule synthesis gene wcaJ, a process mediated by ISKpn26 insertion/deletion or base pair insertion. Spontaneously generated low viscosity variants were also able to compete for hyperviscosity bacteria in the mouse urinary tract.Overall, ISKpn26-dependent viscosity switching in CR-hvKp signals an antibiotic-independent evolution of host adaptation, providing new insights into the role of viscosity switching in CR-hvKp persistence.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a significant clinical threat due to its extensive drug resistance (XDR) and ability to cause serious life-threatening infections.Of particular concern is the emergence of the hypervariant CR-highly pathogenic Kp(CR-hvKp), which exhibits an enhanced virulence factor leading to infections with high mortality. These XDR microorganisms are resistant to almost all clinically available β-lactam antibacterial drugs, of which plasmid-mediated Klebsiella pneumoniae carbapenemase-2 (KPC-2) is the most common class A carbapenemase that causes CR-hvKp. In addition, CR-hvKp can cause a variety of fatal infections, including liver abscesses, bacteremia, and urinary tract infections (UTIs). The high pathogenicity of CR-hvKp is attributed to the presence of mixed conjugative plasmids containing large-scale pathogenic plasmids (such as pLVPK) or both pathogenicity and carbapenem resistance genes.The hardest hit area of the CR-hvKp outbreak is Asia, China is heavily burdened, and ST11 is the most common sequence type.
The pathogenicity of CR-hvKp is significantly enhanced due to pathogenic plasmids containing genes that regulate capsule/viscosity (e. g., rmpADC and rmpA2) and side oxime production (e. g., iucA, iucB, iucC, iucD, iutA).The virulence factors encoded by these plasmids are key biomarkers for CR-hvKp recognition and diagnosis. The high viscosity (HMV) phenotype is a key feature of CR-hvKp resistance to host immune responses, resulting from capsule overexpression and chain length changes mediated by rmpADC/rmpA2. Interestingly, most of the clinically CR-hvKp strains (> amp; gt; 87%) collected from Chinese hospitals showed phenotype-genotype mismatch, mainly low viscosity despite the presence of rmpADC/rmpA2. It is not clear whether these viscosity changes are the result of an evolutionary process within the host. Although these low-viscosity strains are less pathogenic, they have advantages in bacterial adaptability, biofilm formation, and adhesion to epithelial cells and various medical materials, indicating that CR-hvKp viscosity phenotype switching may contribute to their survival in a hospital environment, Persistence in patients or transmission between patients. Depending on the evolution of the patient during antibiotic therapy, the viscosity phenotype switching of the CR-hvKp may be regulated by antibiotic exposure.However, there is a lack of models or cases that confirm the antibiotic irrelevance of this intra-body evolution.
In this study, the authors directly demonstrated for the first time the phenotypic switching of CR-hvKp in patients with urinary tract infections, from high viscosity to low viscosity, and evaluated the impact of this phenotypic evolution on CR-hvKp pathogenicity and colonization. In addition, the mouse urinary tract infection model revealed that this phenotypic switch occurred independently of antibiotic intervention, and the low-viscosity strain showed an advantage in competition with the high-viscosity strain.This work enhances the authors' understanding of how CR-hvKp interact and evolve within the host body, highlighting the potential of targeting viscosity shifts in CR-hvKp infection detection, monitoring, and intervention.
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