Reactive oxygen species drive evolution of pro-biofilm variants in pathogens by modulating cyclic-di-GMP levels.
Reactive oxygen species drive evolution of pro-biofilm variants in pathogens by modulating cyclic-di-GMP levels.
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DOI：
10.1098/rsob.160162
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发表时间：
2016-11
期刊：
影响因子：
5.8
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Chua SL;Ding Y;Liu Y;Cai Z;Zhou J;Swarup S;Drautz-Moses DI;Schuster SC;Kjelleberg S;Givskov M;Yang L
宿主免疫系统提供了一个有害的环境，其中含有对细菌病原体有害的抗菌剂和活性氧物种(ROS)，迫使它们适应和进化以求生存。然而，氧化应激对病原体进化的贡献仍然难以捉摸。利用实验进化策略，我们发现，条件致病菌铜绿假单胞菌暴露在亚致死水平的过氧化氢(H_2O_2)下120代后，会出现亲生物膜粗小菌落变异体(RSCV)，这种变化可以被L-谷胱甘肽抗氧化剂消除。对RSCV的比较基因组分析表明，编码WSPR二鸟苷环化酶(DGC)抑制子的wspF基因突变是导致细胞内环二GMP含量增加和PSL胞外多糖产生的原因。PSL提供了对抗ROS和巨噬细胞的第一道防线，确保了RSCV对野生型铜绿假单胞菌的生存适应性。我们的研究表明，ROS是选择前生物被膜形成致病变异体的重要驱动力。了解这些基因和表型适应的基本机制将改进抗击慢性感染的治疗策略。
The host immune system offers a hostile environment with antimicrobials and reactive oxygen species (ROS) that are detrimental to bacterial pathogens, forcing them to adapt and evolve for survival. However, the contribution of oxidative stress to pathogen evolution remains elusive. Using an experimental evolution strategy, we show that exposure of the opportunistic pathogen Pseudomonas aeruginosa to sub-lethal hydrogen peroxide (H2O2) levels over 120 generations led to the emergence of pro-biofilm rough small colony variants (RSCVs), which could be abrogated by l-glutathione antioxidants. Comparative genomic analysis of the RSCVs revealed that mutations in the wspF gene, which encodes for a repressor of WspR diguanylate cyclase (DGC), were responsible for increased intracellular cyclic-di-GMP content and production of Psl exopolysaccharide. Psl provides the first line of defence against ROS and macrophages, ensuring the survival fitness of RSCVs over wild-type P. aeruginosa. Our study demonstrated that ROS is an essential driving force for the selection of pro-biofilm forming pathogenic variants. Understanding the fundamental mechanism of these genotypic and phenotypic adaptations will improve treatment strategies for combating chronic infections.