铁转运蛋白在高毒力肺炎克雷伯菌致肝脓肿及迁徙性感染中的作用及机制

Community acquired liver abscess caused by hypervirulent Klebsiella pneumoniae (hvKP) is highly prone to be concomitant with sepsis and metastatic infection, this leads to a poor prognosis given its therapeutic difficulty. Although the capsular polysaccharides have long been recognized as the most common and vital virulence factor for the hvKP, the iron acquisition system has been identified as another pivotal virulence factor recently. Nevertheless, the involvement and exact underlying mechanisms of iron-acquisition system in the pathogenesis of liver abscess by hvKP have not been elucidated yet. We have found that the iron-acquisition associated genes were significantly more prevalent in hvKP strains compared to classic Klebsiella pneumoniae (cKP) strains, by comparing the virulence genes between the hvKP strains and cKP strains isolated from pneumonia. Meanwhile, it seems the hvKP strain has a survival advantage over cKP strains in the iron limiting environment. Herein, based on the already collected 30 cKP strains isolated from pneumonia and another 30 hvKP strains isolated from the liver abscess or metastatic infection, the involvement of iron-acquisition system in the pathogenesis of liver abscess and concomitant metastatic infection caused by hvKP would be explored in this study. By using technologies including comparative genomics technology, in vivo imaging system, gene knockout and genetic complementation, liver abscess model in db/db diabetic mice, and in vivo transcriptional profiling, the relationship between iron-acquisition system and the high virulence and high rates of metastatic infection of hvKP would be disclosed. This finding will thus help us to develop new therapeutic strategy and eventually improve clinical outcomes.

高毒力肺炎克雷伯菌(hvKP)导致的社区获得性肝脓肿极易并发脓毒血症及迁徙性感染，治疗困难，临床预后差。荚膜多糖一直被认为是hvKP最常见和最主要的致病因子，近年研究发现铁转运相关基因分布与hvKP高致病力密切相关，铁转运蛋白被认为是新的重要毒力因子，但其确切的致病作用和机制不清。本课题组前期研究发现我国流行的hvKP菌株中铁转运相关基因携带率显著升高，且在限铁环境中存在明显生存优势。本课题拟以临床收集的30株传统肺炎克雷伯菌和30株肝脓肿及迁徙性病灶分离菌株为研究对象，采用比较基因组学、活体动物成像、基因敲除和回补、小鼠肝脓肿模型、转录组学等技术，从感染能力、致肝脓肿能力及与宿主交互作用等方面阐明铁转运蛋白在肺炎克雷伯菌致肝脓肿及迁徙性感染中的作用及机制，为探索hvKP感染治疗新策略，改善hvKP感染临床预后提供科学基础。

高毒力肺炎克雷伯菌(hvKP)导致的社区获得性肝脓肿极易并发脓毒血症及迁徙性感染，治疗困难，临床预后差。近年研究发现铁转运相关基因分布与hvKP高致病力密切相关，铁转运蛋白被认为是新的重要毒力因子，但其确切的致病作用和机制不清。本课题以临床收集的传统肺炎克雷伯菌和肝脓肿及迁徙性病灶分离菌株为研究对象，采用比较基因组学、活体动物成像、基因敲除和回补、小鼠肝脓肿模型、转录组学等技术，发现hvKP组铁转运相关基因Kfu,iroN,iutA携带率也显著高于cKP组，血行感染分离的肺炎克雷伯菌clb携带率显著高于院内获得性感染分离菌株；同时菌株分泌铁载体的种类的增加，菌株的黏性水平也随之增加，初步明确了铁转运基因与hvKP菌株高毒力及高迁徙性感染能力的关系。研究从感染能力、致肝脓肿能力及与宿主交互作用等方面初步阐明铁转运蛋白在肺炎克雷伯菌致肝脓肿及迁徙性感染中的作用及机制。为挖掘hvKP临床感染治疗新策略及改善hvKP感染临床预后提供科学基础。