Jianping Jiang, Leilei Wang, Yiyi Hu, Xin Chen, Pei Li, Jianfeng Zhang, Yixin Zhang, Jiachun Su, Xiaogang Xu, Yonghong Xiao, Zhengyin Liu, Yunsong Yu, Hainv Gao, Yohei Doi, David van Duin, Vance G Fowler, Liang Chen, Minggui Wang
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引用次数: 0
摘要
背景：碳青霉烯耐药高致病性肺炎克雷伯菌（CR-hvKp）在世界范围内的报道越来越多，对公共卫生构成严重挑战；然而，推动其出现和全球传播的机制仍不清楚。方法对来自典型hvKp背景的CR-hvKp菌株进行分析，获得碳青霉烯酶编码基因。这些菌株是从CRACKLE-2中国队列中的485株CRKp分离株、多中心研究中的259株CRKp分离株和GenBank中提供的67,631株肺炎克雷伯菌基因组中鉴定出来的。选择含有IncFIIK34 KPC-2质粒的临床分离株进行基因组测序、RNA-Seq、偶联分析、体内、体外和体外表型表征。结果：对来自24个国家的临床CR-hvKp分离株和GenBank中可获得的414个基因组进行分析，发现IncFIIK34 KPC-2质粒是流行的KPC质粒（在产生KPC的CR-hvKp中检测到25%，45/178）。与流行的IncFIIK2 KPC-2质粒相比，IncFIIK34 KPC-2质粒的偶联频率增加了100至1000倍（10-4-10-5 vs. 10-7），并且在美罗培南挑战下具有体外生长优势，这可能是由于偶联相关基因的过表达以及blaKPC拷贝数和表达的增加。携带该质粒的CR-hvKp分离物和hvKp转偶联物在小鼠模型和人中性粒细胞试验中经常表现出黏性降低，同时保持高毒力。IncFIIK34质粒可能是推动CR-hvKp全球传播的关键因素，强调了加强对这种新兴病原体的分子监测的迫切需要。资助：国家自然科学基金和国家卫生研究院。
Global emergence of Carbapenem-resistant Hypervirulent Klebsiella pneumoniae driven by an IncFIIK34 KPC-2 plasmid.
Background: Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) has been increasingly reported worldwide, posing a severe challenge to public health; however, the mechanisms driving its emergence and global dissemination remain unclear.
Methods: We analysed CR-hvKp strains derived from canonical hvKp backgrounds, and acquired a carbapenemase-encoding gene. These strains were identified from 485 CRKp isolates in the CRACKLE-2 China cohort, 259 CRKp isolates from a multi-centre study, and 67,631 K. pneumoniae genomes available in GenBank. Clinical isolates harbouring the IncFIIK34 KPC-2 plasmid were selected for genome sequencing, RNA-Seq, conjugation assays, in vivo, ex vivo, and in vitro phenotypic characterisation.
Findings: Analysis of clinical CR-hvKp isolates and the 414 genomes from 24 countries available in GenBank identified an IncFIIK34 KPC-2 plasmid as the prevalent KPC plasmid (detected in 25%, 45/178 of KPC-producing CR-hvKp). Compared with the epidemic IncFIIK2 KPC-2 plasmid, the IncFIIK34 KPC-2 plasmid exhibited a 100- to 1000-fold increase in conjugation frequency (10-4-10-5 vs. 10-7) and an in vitro growth advantage under meropenem challenge-likely due to the overexpression of conjugation-related genes and an increased blaKPC copy number and expression. CR-hvKp isolates and hvKp transconjugants carrying this plasmid often exhibited reduced mucoviscosity, while retaining hypervirulence in both murine models and human neutrophil assays.
Interpretation: The IncFIIK34 plasmid may be a key factor driving the global dissemination of CR-hvKp, underscoring the urgent need for enhanced molecular surveillance of this emerging pathogen.
Funding: National Natural Science Foundation of China and National Institutes of Health.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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