PDF(Pubmed)
Abstract：
The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a growing concern due to its high mortality and limited treatment options. Although hypermucoviscosity is crucial for CR-hvKp infection, the role of changes in bacterial mucoviscosity in the host colonization and persistence of CR-hvKp is not clearly defined. Herein, we observed a phenotypic switch of CR-hvKp from a hypermucoviscous to a hypomucoviscous state in a patient with scrotal abscess and urinary tract infection (UTI). This switch was attributed to decreased expression of rmpADC, the regulator of mucoid phenotype, caused by deletion of the upstream insertion sequence ISKpn26. Postswitching, the hypomucoid variant showed a 9.0-fold decrease in mice sepsis mortality, a >170.0-fold reduction in the ability to evade macrophage phagocytosis in vitro, and an 11.2- to 40.9-fold drop in growth rate in normal mouse serum. Conversely, it exhibited an increased residence time in the mouse urinary tract (21 vs. 6 d), as well as a 216.4-fold boost in adhesion to bladder epithelial cells and a 48.7% enhancement in biofilm production. Notably, the CR-hvKp mucoid switch was reproduced in an antibiotic-free mouse UTI model. The in vivo generation of hypomucoid variants was primarily associated with defective or low expression of rmpADC or capsule synthesis gene wcaJ, mediated by ISKpn26 insertion/deletion or base-pair insertion. The spontaneous hypomucoid variants also outcompeted hypermucoid bacteria in the mouse urinary tract. Collectively, the ISKpn26-associated mucoid switch in CR-hvKp signifies the antibiotic-independent host adaptive evolution, providing insights into the role of mucoid switch in the persistence of CR-hvKp.
摘要：
碳青霉烯类耐药高毒力肺炎克雷伯菌（CR-hvKp）的出现由于其高死亡率和有限的治疗选择而日益受到关注。尽管高粘膜粘度对CR-hvKp感染至关重要，细菌粘膜粘度变化在CR-hvKp宿主定植和持久性中的作用尚不明确.在这里，在阴囊脓肿和尿路感染(UTI)患者中,我们观察到CR-hvKp从高粘膜粘稠状态向低粘膜粘稠状态的表型转换.这种转换归因于rmpADC的表达减少，粘液表型的调节因子，由上游插入序列ISKpn26的缺失引起。后置切换,低黏蛋白变体显示小鼠败血症死亡率降低9.0倍，在体外逃避巨噬细胞吞噬的能力降低>170.0倍，正常小鼠血清中的生长速率下降11.2至40.9倍。相反，它在小鼠泌尿道中的停留时间增加(21vs.6d),以及对膀胱上皮细胞的粘附增加216.4倍，生物膜产生增加48.7％。值得注意的是,CR-hvKp粘液样开关在无抗生素小鼠UTI模型中再现.体内产生的类粘液变体主要与rmpADC或被膜合成基因wcaJ的缺陷或低表达有关，由ISKpn26插入/缺失或碱基对插入介导。在小鼠泌尿道中，自发的低粘液变体也胜过高粘液细菌。总的来说，CR-hvKp中与ISKpn26相关的粘液样开关表示不依赖抗生素的宿主适应性进化，提供对黏液开关在CR-hvKp持续中的作用的见解。
