MprA and DosR Coregulate a Mycobacterium tuberculosis Virulence Operon Encoding Rv1813c and Rv1812c
MprA and DosR Coregulate a Mycobacterium tuberculosis Virulence Operon Encoding Rv1813c and Rv1812c
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DOI：
10.1128/iai.00520-12
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发表时间：
2012-09-01
影响因子：
3.1
通讯作者：
Zahrt, Thomas C.
中科院分区：
文献类型：
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作者：
Bretl, Daniel J.;He, Hongjun;Zahrt, Thomas C.
结核分枝杆菌仍然是一种重要的全球病原体，在世界范围内造成广泛的发病率和死亡率。这种细菌在肉芽肿性皮损中持续存在，特征不佳，不能复制。双组分信号转导系统MprAB和DosRS-Dost(DevRS-Rv2027c)对可能出现在肉芽肿性病变内的条件做出反应，并在体外和体内介导结核分枝杆菌持久性的方面。在这里，我们描述了一个以前未描述的基因座Rv1813c-Rv1812c，它由MprA和DosR共同调节。我们证明MprA和DosR与Rv1813c启动子区域内的相邻和重叠序列结合，并从位于Rv1813翻译起始点上游的数百个碱基对的起始点直接转录。我们进一步证明Rv1813c和Rv1812c是共转录的，并且这个操纵子的基因组组织是结核分枝杆菌和牛分枝杆菌所特有的。虽然Rv1813c不是结核分枝杆菌在体外存活所必需的，包括在MprAB和DosRST信号被激活的条件下，但结核分枝杆菌Delta Rv1813c突变株在小鼠结核病的低剂量气雾剂模型中被减弱，在那里它表现出更低的细菌负荷，延迟死亡时间，并降低刺激促炎细胞因子IL-1β(IL-1β)和IL-12的能力。有趣的是，在结核分枝杆菌Delta Rv1813c突变体中观察到这些表型的过度互补，Rv1813c同时表达Rv1813c和Rv1812c，但不只表达Rv1813c。因此，Rv1813c和Rv1812c可能代表了结核分枝杆菌毒力和宿主对感染的免疫反应所必需的一般应激反应元件。
Mycobacterium tuberculosis remains a significant global pathogen, causing extensive morbidity and mortality worldwide. This bacterium persists within granulomatous lesions in a poorly characterized, nonreplicating state. The two-component signal transduction systems MprAB and DosRS-DosT (DevRS-Rv2027c) are responsive to conditions likely to be present within granulomatous lesions and mediate aspects of M. tuberculosis persistence in vitro and in vivo. Here, we describe a previously uncharacterized locus, Rv1813c-Rv1812c, that is coregulated by both MprA and DosR. We demonstrate that MprA and DosR bind to adjacent and overlapping sequences within the promoter region of Rv1813c and direct transcription from an initiation site located several hundred base pairs upstream of the Rv1813 translation start site. We further show that Rv1813c and Rv1812c are cotranscribed, and that the genomic organization of this operon is specific to M. tuberculosis and Mycobacterium bovis. Although Rv1813c is not required for survival of M. tuberculosis in vitro, including under conditions in which MprAB and DosRST signaling are activated, an M. tuberculosis Delta Rv1813c mutant is attenuated in the low-dose aerosol model of murine tuberculosis, where it exhibits a lower bacterial burden, delayed time to death, and decreased ability to stimulate proinflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-12. Interestingly, overcomplementation of these phenotypes is observed in the M. tuberculosis Delta Rv1813c mutant expressing both Rv1813c and Rv1812c, but not Rv1813c alone, in trans. Therefore, Rv1813c and Rv1812c may represent general stress-responsive elements that are necessary for aspects of M. tuberculosis virulence and the host immune response to infection.