Loughlin Michael F, Arandhara Victoria, Okolie Charles, Aldsworth Timothy G, Jenks Peter J
Institute of Infection, Immunity and Inflammation, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Microb Pathog. 2009 Jan;46(1):53-7. doi: 10.1016/j.micpath.2008.10.004. Epub 2008 Nov 1.
The ATP-dependent caseinolytic proteases (Clp) are important in resistance against environmental stresses, antibiotic treatments and host immune defences for a number of pathogenic bacteria. ClpP is the proteolytic subunit, whilst ClpA acts both as a chaperone and as an ATPase driving the degradation of damaged or mis-made proteins. The gastric pathogen Helicobacter pylori infects approximately half of the world's population and can cause gastric or duodenal ulcers, gastric malignancies and mucosa-associated lymphoid tissue lymphomas. The conditions of its in vivo environment expose the organism to host immune cells and upon treatment, antibiotics, conditions likely to cause protein damage. We generated isogenic nonpolar mutants in strain SS1 of clpP and clpA and double mutants with both genes inactivated. Such mutants showed increased sensitivity to antibacterials causing protein damage and/or oxidative stress, in addition to a reduced survival in human macrophages. In the mouse infection model the double mutant SS1 clpAP lacked all ability to colonize the murine host. This suggests that the ability to recover from protein damage is of key importance in the pathogenesis of this organism.
ATP 依赖性酪蛋白水解蛋白酶（Clp）对于许多致病细菌抵抗环境压力、抗生素治疗和宿主免疫防御至关重要。ClpP 是蛋白水解亚基，而 ClpA 既作为伴侣蛋白又作为 ATP 酶，驱动受损或错误合成蛋白质的降解。胃部病原体幽门螺杆菌感染了全球约一半的人口，可导致胃溃疡、十二指肠溃疡、胃部恶性肿瘤和黏膜相关淋巴组织淋巴瘤。其体内环境状况使该生物体暴露于宿主免疫细胞以及治疗时的抗生素之下，这些情况都可能导致蛋白质损伤。我们在 clpP 和 clpA 的 SS1 菌株中产生了同基因非极性突变体以及两个基因均失活的双突变体。这些突变体除了在人类巨噬细胞中的存活率降低外，对导致蛋白质损伤和/或氧化应激的抗菌药物表现出更高的敏感性。在小鼠感染模型中，双突变体 SS1 clpAP 完全丧失了定殖于小鼠宿主的能力。这表明从蛋白质损伤中恢复的能力在该生物体的发病机制中至关重要。
