iroBCDN 缺失的 pLVPK 样质粒在我国最流行的高毒力碳青霉烯类耐药 ST11-KL64 肺炎克雷伯菌进化中的关键作用。
The key role of iroBCDN-lacking pLVPK-like plasmid in the evolution of the most prevalent hypervirulent carbapenem-resistant ST11-KL64 Klebsiella pneumoniae in China.
机构信息
Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Center for bioinformatics, National Infrastructures for Translational Medicine, Institute of Clinical Medicine & Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
出版信息
Drug Resist Updat. 2024 Nov;77:101137. doi: 10.1016/j.drup.2024.101137. Epub 2024 Aug 14.
AIMS
Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP), coharboring hypervirulence and carbapenem-resistance genes mediated by plasmids, causes infections with extremely high mortality and seriously impacts public health. Exploring the transfer mechanisms of virulence/carbapenem-resistance plasmids, as well as the formation and evolution pathway of hv-CRKP is of great significance to the control of hv-CRKP infections.
METHODS
In this study, we identified the predominant clone of hv-CRKP in China and elucidated its genomic characteristics and formation route based on 239 multicenter clinical K. pneumoniae isolates and 1014 GenBank genomes by using comparative genomic analysis. Further, we revealed the factors affecting the transfer of virulence plasmids, and explained the genetic foundation for the prevalence of Chinese predominant hv-CRKP clone.
RESULTS
ST11-KL64 is the predominant clone of hv-CRKP in China and primarily evolved from ST11-KL64 CRKP by acquiring the pLVPK-like virulence plasmid from hvKP. Significantly, the virulence gene cluster iroBCDN was lost in the virulence plasmid of ST11-KL64 hv-CRKP but existed in that of hvKP. Moreover, the absence of iroBCDN didn't decrease the virulence of hv-CRKP, which was proved by bacterial test, cell-interaction test and mice infection model. On the contrary, loss of iroBCDN was observed to regulate virulence/carbapenem-resistance plasmid transfer and oxidative stress-related genes in strains and thus promoted the mobilization of nonconjugative virulence plasmid from hvKP into ST11-KL64 CRKP, forming hv-CRKP which finally had elevated antioxidant capacity and enhanced survival capacity in macrophages. The loss of iroBCDN increased the survival ability of hv-CRKP without decreasing its virulence, endowing it with an evolutionary advantage.
CONCLUSIONS
Our work provides new insights into the key role of iroBCDN loss in convergence of CRKP and hvKP, and the genetic and biological foundation for the widespread prevalence of ST11-KL64 hv-CRKP in China.
目的
产超广谱β-内酰胺酶（ESBLs）、携带质粒介导的高毒力和碳青霉烯类耐药基因的高毒力碳青霉烯类耐药肺炎克雷伯菌（hv-CRKP）引起的感染具有极高的死亡率，严重影响公共健康。探索毒力/碳青霉烯类耐药质粒的转移机制，以及 hv-CRKP 的形成和进化途径，对控制 hv-CRKP 感染具有重要意义。
方法
本研究通过对 239 株多中心临床分离的肺炎克雷伯菌和 1014 株 GenBank 基因组进行比较基因组分析，确定了中国 hv-CRKP 的主要流行克隆，并阐明了其基因组特征和形成途径。进一步揭示了影响毒力质粒转移的因素，并解释了中国主要 hv-CRKP 克隆流行的遗传基础。
结果
ST11-KL64 是中国 hv-CRKP 的主要流行克隆，主要由 ST11-KL64 CRKP 通过从 hvKP 获得 pLVPK 样毒力质粒进化而来。值得注意的是，毒力基因簇 iroBCDN 在 ST11-KL64 hv-CRKP 的毒力质粒中丢失，但存在于 hvKP 中。此外，iroBCDN 的缺失并没有降低 hv-CRKP 的毒力，这一点通过细菌试验、细胞相互作用试验和小鼠感染模型得到了证实。相反，iroBCDN 的缺失被观察到可以调节菌株中毒力/碳青霉烯类耐药质粒的转移和氧化应激相关基因，从而促进非接合性毒力质粒从 hvKP 转移到 ST11-KL64 CRKP 中，形成 hv-CRKP，最终使其具有更高的抗氧化能力和增强在巨噬细胞中的存活能力。iroBCDN 的缺失增加了 hv-CRKP 的存活能力，而没有降低其毒力，赋予了它进化优势。
结论
本研究工作为 iroBCDN 缺失在 CRKP 和 hvKP 融合中的关键作用提供了新的见解，并为中国 ST11-KL64 hv-CRKP 的广泛流行提供了遗传和生物学基础。
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