Strains of the East Asian (W/Beijing) Lineage of Mycobacterium tuberculosis Are DosS/DosT-DosR Two-Component Regulatory System Natural Mutants
Strains of the East Asian (W/Beijing) Lineage of Mycobacterium tuberculosis Are DosS/DosT-DosR Two-Component Regulatory System Natural Mutants
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DOI：
10.1128/jb.01597-09
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发表时间：
2010-04-15
影响因子：
3.2
通讯作者：
Reed, Michael B.
中科院分区：
文献类型：
--
作者：
Fallow, Ashley;Domenech, Pilar;Reed, Michael B.
作为我们不断努力揭示临床结核分枝杆菌分离株遗传变异性表型后果的一部分，我们之前报道过“东亚”或“W/北京”谱系的分离株在标准体外条件下组成性过度表达被称为DosR调节子的协调调节转录程序。这种表型将 W/Beijing 谱系与所有其他结核分枝杆菌谱系区分开来，后者通常仅在暴露于低氧或一氧化氮时诱导该调节子的表达，这两者都会导致细菌呼吸和复制的抑制。 DosR 调节子的转录是通过双组分调节系统控制的，该系统包括转录因子 DosR 和两种可能的同源组氨酸传感器激酶 DosS 和 DosT。通过对代表每个主要结核分枝杆菌谱系的精心挑选的一组分离株进行序列分析，我们在此描述了最近进化的W/北京亚谱系分离株的编码DosT传感器激酶的基因中自然发生的移码突变。有趣的是，移码突变的发生与相同“现代”W/北京菌株所表现出的组成型 DosR 调节子表型的出现精确相关。然而，互补研究表明，单独的 dosT 突变并不直接导致 DosR 调节子表型。我们的数据旨在强调不同结核分枝杆菌谱系之间存在的进化压力，以保持对 DosR 调节子表达的严格控制。
As part of our ongoing efforts to uncover the phenotypic consequences of genetic variability among clinical Mycobacterium tuberculosis isolates, we previously reported that isolates of the "East Asian" or "W/Beijing" lineage constitutively overexpress the coordinately regulated transcriptional program known as the DosR regulon under standard in vitro conditions. This phenotype distinguishes the W/Beijing lineage from all other M. tuberculosis lineages, which normally induce expression of this regulon only once exposed to low oxygen or nitric oxide, both of which result in inhibition of bacterial respiration and replication. Transcription of the DosR regulon is controlled through a two-component regulatory system comprising the transcription factor DosR and two possible cognate histidine sensor kinases, DosS and DosT. Through sequence analysis of a carefully selected set of isolates representing each of the major M. tuberculosis lineages, we describe herein a naturally occurring frameshift mutation in the gene encoding the DosT sensor kinase for isolates of the most recently evolved W/Beijing sublineages. Intriguingly, the occurrence of the frameshift mutation correlates precisely with the appearance of the constitutive DosR regulon phenotype displayed by the same "modern" W/Beijing strains. However, complementation studies have revealed that the mutation in dosT alone is not directly responsible for the constitutive DosR regulon phenotype. Our data serve to highlight the evolutionary pressure that exists among distinct M. tuberculosis lineages to maintain tight control over DosR regulon expression.