铁摄取介导的细菌/宿主肝吞噬细胞铁平衡在肺炎克雷伯菌致肝脓肿发病及诊断中的研究

Klebsiella pneumoniae is a well-known human nosocomial pathogen. The Klebsiella pneumoniae-caused liver abscess (KLA) has become a health problem and the mechanism is still poorly understood. Iron is an essential trace element for multicellular organisms and microorganisms. In our preliminary work, we sequenced LA-Kp, and found iroBCD is specific in LA-Kp, but not in non LA-Kp. The iroBCD positive LA-Kp strain showed hype-proliferation in low-iron medium. Furthermore, we also found upregulation of cellular total iron level and IL-6 expression in LA-Kp infected murine macrophage J774A.1 cell line in vitro, compared with non LA-Kp infected cells. Thus, the hypothesis in our proposal is, the interaction between host IL-6/Stat3 axis in controlling iron-regulation and iroBCD mediated iron transportation in LA-Kp is crucial for development of liver abscess. We are going to use the iroBCD KO LA-Kp strain, Stat-3f/f LyZ Cre+ mice to investigate the mechanism of host defense in KLA mediated by iron uptake in pathogens and host.

肺炎克雷伯菌（Kp）是肝脓肿（LA）重要的致病菌，其多种致病因子与感染相关，但致病机制仍未阐明。铁是细菌和宿主维持正常生理功能的重要成分。近年来发现铁转运相关基因与Kp的毒力密切相关。我们前期对致LA-Kp菌株和非LA-Kp菌株测序发现，LA-Kp有特异的铁转运基因iroBCD。同时还发现LA-Kp在低铁条件生长显著快于非LA-Kp，且LA-Kp体外感染小鼠巨噬细胞胞内总铁含量及IL-6水平显著高于非LA-Kp感染组。我们推测，宿主吞噬细胞IL-6/Stat3铁调信号与LA-Kp iroBCD铁转运互作是肝脓肿发生的关键。我们拟通过构建iroBCD敲除株及Stat3髓系细胞条件敲除小鼠肝脓肿模型（消化道感染、败血症并发肝脓肿）等来研究病原菌和宿主铁摄取互作的感染与抗感染机制，并结合临床样本检测，阐明LA-Kp致肝脓肿致病的关键因素和节点，为临床该病诊治提供新思路。

铁是细菌和宿主维持正常生理功能的重要成分。近年来发现铁转运相关基因与Kp的毒力密切相关。目前，有关铁条系统在LAKp感染和宿主互作中的作用和机制尚未明确。本研究通过测序、构建LAKp感染的体内外模型，检测LA患者外周血免疫细胞等，发现LAKp中存在多条铁转运系统和高毒力相关基因；LAKp感染会导致巨噬细胞铁调系统相关通路调控基因表达上调和M1/M2极化失衡，并能破坏巨噬细胞中溶酶体。NLRP3可能是Stat3的上游信号，亦是调控上述过程的关键分子。另一方面，LAKp能导致健康人PBMC中Th1/Th2失衡，且LA患者血浆中Th2相关的炎症因子水平亦显著上调。本研究揭示了铁调系统在联系病原菌、宿主天然免疫应答和适应性免疫应答中的作用和新机制，为寻找LAKp感染的诊治提供新策略。