Li Mei, Long Yuqing, Liu Ying, Liu Yang, Chen Ronghao, Shi Jing, Zhang Lu, Jin Yongxin, Yang Liang, Bai Fang, Jin Shouguang, Cheng Zhihui, Wu Weihui
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University Tianjin, China.
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University Singapore, Singapore.
Front Cell Infect Microbiol. 2016 Oct 14;6:125. doi: 10.3389/fcimb.2016.00125. eCollection 2016.
Bacterial persister cells are dormant and highly tolerant to lethal antibiotics, which are believed to be the major cause of recurring and chronic infections. Activation of toxins of bacterial toxin-antitoxin systems inhibits bacterial growth and plays an important role in persister formation. However, little is known about the overall gene expression profile upon toxin activation. More importantly, how the dormant bacterial persisters evade host immune clearance remains poorly understood. Here we demonstrate that a toxin-antitoxin system HigB-HigA is required for the ciprofloxacin induced persister formation. Transcriptome analysis of a ::Tn mutant revealed up regulation of type III secretion systems (T3SS) genes. Overexpression of HigB increased the expression of T3SS genes as well as bacterial cytotoxicity. We further demonstrate that wild type bacteria that survived ciprofloxacin treatment contain higher levels of T3SS proteins and display increased cytotoxicity to macrophage compared to vegetative bacterial cells. These results suggest that accumulates T3SS proteins during persister formation, which can protect the persister cells from host clearance by efficiently killing host immune cells.
细菌持留菌细胞处于休眠状态，对致死性抗生素具有高度耐受性，据信这是反复感染和慢性感染的主要原因。细菌毒素-抗毒素系统的毒素激活会抑制细菌生长，并在持留菌形成中起重要作用。然而，关于毒素激活后的整体基因表达谱知之甚少。更重要的是，休眠的细菌持留菌如何逃避宿主免疫清除仍知之甚少。在这里，我们证明了毒素-抗毒素系统HigB-HigA是环丙沙星诱导持留菌形成所必需的。对一个::Tn突变体的转录组分析显示III型分泌系统（T3SS）基因上调。HigB的过表达增加了T3SS基因的表达以及细菌的细胞毒性。我们进一步证明，与营养态细菌细胞相比，在环丙沙星处理后存活的野生型细菌含有更高水平的T3SS蛋白，并且对巨噬细胞显示出增加的细胞毒性。这些结果表明，在持留菌形成过程中积累了T3SS蛋白，这可以通过有效杀死宿主免疫细胞来保护持留菌细胞免受宿主清除。
