Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis
Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis
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DOI：
10.1128/jb.00696-16
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发表时间：
2017-01-01
影响因子：
3.2
通讯作者：
Reed, Michael B.
中科院分区：
文献类型：
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作者：
Domenech, Pilar;Zou, Jason;Reed, Michael B.
DosR调控是结核分枝杆菌在抑制有氧呼吸条件下通常表达的一组48个基因，通过DosR- doss /DosT双组分系统进行控制。虽然该调控在大多数结核分枝杆菌分离株中需要诱导，但对于北京谱系的成员，其表达与信号传递的需要是分离的。在我们试图了解北京背景下这种解耦的机制基础时，我们之前报道了在邻近的Rv3134c基因中鉴定出两个同义的单核苷酸多态性（snp）。在本研究中，我们研究了这些snp对北京和非北京结核分枝杆菌野生型菌株以及一系列dos- rdos - dost突变体中dosR表达的影响。通过这种方式，我们明确地确定了C601T dosR启动子SNP是在这个全球重要谱系中看到的dosR调控表达模式发生巨大变化的唯一要求。有趣的是，我们还表明，在这些菌株中，DosT完全不起作用。因此，一系列复杂的进化步骤导致了今天的北京DosR表型，这反过来又可能在面对某种形式的宿主相关选择压力时赋予适应性优势。重要性北京结核分枝杆菌菌株与其他菌株相比具有更强的毒力，并且在某些地区，它们与耐多药结核病（TB）的急剧传播有关。在试图理解这些广泛流行病学现象的功能基础方面，有趣的是，与其他主要谱系相比，北京菌株都构成性地过度表达DosR规则的成员。在这里，我们确定了导致这种独特表型进化的突变事件。此外，我们的工作强调了这样一个事实，即不同结核分枝杆菌谱系之间存在重要的表型差异，这可能会影响诊断、疫苗接种和治疗方案的有效性。
The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dos-RdosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure.IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.