Hypermutation-induced in vivo oxidative stress resistance enhances Vibrio cholerae host adaptation.
Hypermutation-induced in vivo oxidative stress resistance enhances Vibrio cholerae host adaptation.
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DOI：
10.1371/journal.ppat.1007413
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Wang H;Xing X;Wang J;Pang B;Liu M;Larios-Valencia J;Liu T;Liu G;Xie S;Hao G;Liu Z;Kan B;Zhu J
细菌性病原体是适应性很强的生物体，这种特性使它们能够克服不断变化的敌对环境。例如，霍乱病原体霍乱弧菌能够在宿主小肠定植，并在感染期间对抗宿主产生的活性氧（ROS）。为了剖析霍乱弧菌在体内克服ROS的分子机制，我们进行了全基因组转座子测序分析（Tn-seq），通过比较使用和不使用抗氧化剂n-乙酰半胱氨酸处理的成年小鼠定植的基因需求。我们发现甲基定向错配修复（MMR）系统的突变体，如MutS，在未处理的富含ros的小鼠中表现出显著的定植优势，而在nac处理的小鼠中则没有。进一步的分析表明，NAC-小鼠体内过氧化氢酶过量突变体和rugose菌落变异的积累是感染期间氧化应激引起的mutS突变体富集的主要原因。我们还发现，在有氧体外培养中，rugose变异可以恢复到光滑的菌落。此外，NAC-小鼠定殖的野生型突变率显著高于NAC+小鼠。综上所述，这些发现支持了一种范式，即霍乱弧菌在感染期间采用一种时间适应性策略来对抗ROS，从而导致表型丰富。此外，ΔmutS传代和互补可用于模拟不同病原体的超突变，以确定新的抗逆性机制。霍乱是一种毁灭性的腹泻疾病，在许多发展中国家仍然流行，最近在也门发生了历史上最严重的疫情。霍乱的病原体霍乱弧菌从水生宿主转移到人的胃肠道，在那里表达毒力因子，促进小肠定植，并对抗宿主的先天免疫效应物，如活性氧（ROS）。我们应用全基因组转座子筛选（Tn-seq）发现，作为DNA错配修复系统的一部分，mutS的缺失极大地增加了ros -富小鼠的定植。当体内暴露于ROS选择压力时，mutS的缺失导致过氧化氢酶过量突变体的积累和高频皱皱病表型。此外，ROS在体外和体内都提高了野生型的突变频率。我们的数据暗示霍乱弧菌可能调节突变频率作为克服氧化应激和增强传染性的时间适应性策略。
Bacterial pathogens are highly adaptable organisms, a quality that enables them to overcome changing hostile environments. For example, Vibrio cholerae, the causative agent of cholera, is able to colonize host small intestines and combat host-produced reactive oxygen species (ROS) during infection. To dissect the molecular mechanisms utilized by V. cholerae to overcome ROS in vivo, we performed a whole-genome transposon sequencing analysis (Tn-seq) by comparing gene requirements for colonization using adult mice with and without the treatment of the antioxidant, N-acetyl cysteine. We found that mutants of the methyl-directed mismatch repair (MMR) system, such as MutS, displayed significant colonization advantages in untreated, ROS-rich mice, but not in NAC-treated mice. Further analyses suggest that the accumulation of both catalase-overproducing mutants and rugose colony variants in NAC- mice was the leading cause of mutS mutant enrichment caused by oxidative stress during infection. We also found that rugose variants could revert back to smooth colonies upon aerobic, in vitro culture. Additionally, the mutation rate of wildtype colonized in NAC- mice was significantly higher than that in NAC+ mice. Taken together, these findings support a paradigm in which V. cholerae employs a temporal adaptive strategy to battle ROS during infection, resulting in enriched phenotypes. Moreover, ΔmutS passage and complementation can be used to model hypermuation in diverse pathogens to identify novel stress resistance mechanisms. Cholera is a devastating diarrheal disease that is still endemic to many developing nations, with the worst outbreak in history having occurred recently in Yemen. Vibrio cholerae, the causative agent of cholera, transitions from aquatic reservoirs to the human gastrointestinal tract, where it expresses virulence factors to facilitate colonization of the small intestines and to combat host innate immune effectors, such as reactive oxygen species (ROS). We applied a genome-wide transposon screen (Tn-seq) and identified that deletion of mutS, which is part of DNA mismatch repair system, drastically increased colonization in ROS-rich mice. The deletion of mutS led to the accumulation of catalase-overproducing mutants and a high frequency rugose phenotype when exposed to ROS selective pressures in vivo. Additionally, ROS elevated mutation frequency in wildtype, both in vitro and in vivo. Our data imply that V. cholerae may modulate mutation frequency as a temporal adaptive strategy to overcome oxidative stress and to enhance infectivity.
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影响因子：
56.9
作者：
Giraud, A;Matic, I;Taddei, F
通讯作者：
Taddei, F
影响因子：
3.6
作者：
BASSLER, BL;WRIGHT, M;SILVERMAN, MR
通讯作者：
SILVERMAN, MR
影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1016/j.bbagen.2003.10.016
发表时间：
2004-01-05
影响因子：
3
作者：
Bhattacharyya, S;Ghosh, S;Majumdar, S
通讯作者：
Majumdar, S
影响因子：
4.5
作者：
Didelot X;Pang B;Zhou Z;McCann A;Ni P;Li D;Achtman M;Kan B
通讯作者：
Kan B