M. tuberculosis AlkX Encoded by rv3249c Regulates a Conserved Alkane Hydroxylase System That Is Important for Replication in Macrophages and Biofilm Formation.
M. tuberculosis AlkX Encoded by rv3249c Regulates a Conserved Alkane Hydroxylase System That Is Important for Replication in Macrophages and Biofilm Formation.
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DOI：
10.1128/spectrum.01969-22
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发表时间：
2022-08-31
影响因子：
3.7
通讯作者：
Purdya, Georgiana E.
中科院分区：
文献类型：
--
作者：
Stokas, Haley;Rhodes, Heather L.;Simmons, Marit B.;Zhang, Richard;Wright, Catherine C.;Purdya, Georgiana E.
结核分枝杆菌是一种高度专门化的人类病原体。结核分枝杆菌的成功是因为它能够在宿主巨噬细胞内复制，抵抗宿主免疫反应，并最终在潜伏的结核病感染期间进入持续状态。了解结核分枝杆菌如何适应和复制宿主的细胞内环境，对于开发新的靶向治疗方法至关重要。我们报告了一个缺乏TetR转录调节因子Rv3249c的结核分枝杆菌突变株的特征。我们发现Rv3249c直接抑制了编码烷烃羟基酶/Rubredosin系统的相邻的B-Ruba-Rubb操纵子。为了与相关系统保持一致，我们将rv3249c基因命名为alkX。在巨噬细胞内，alkX突变体比野生型结核分枝杆菌存活得更好。这可能是由于alkB-Ruba-Rubb基因的过度表达所致。我们假设，细胞内存活表型的改善是突变体适合度增加的结果；然而，我们在体外发现，当在一些与宿主相关的碳源上生长时，alkX突变体存在缺陷。我们还发现，alkX突变体在生物膜形成方面存在缺陷，这也与alkB-rubab基因的过度表达有关。综上所述，这些结果确定了AlkX作为alkB-rubab操纵子的转录抑制因子的主要作用，并表明该操纵子有助于病原体的细胞内生存。结核分枝杆菌是结核病(TB)的病原体，是世界范围内因单一感染性病原体而导致死亡的主要原因。了解结核分枝杆菌如何适应和复制宿主的细胞内环境是很重要的。在这项研究中，我们对TetR转录调控因子Rv3249c进行了鉴定，并表明它调控着一个高度保守的烷烃羟基酶/Rubredosin系统。我们的数据表明，AlkBRubAB系统有助于细菌在宿主巨噬细胞中的成功。
Mycobacterium tuberculosis is a highly specialized human pathogen. The success of M. tuberculosis is due to its ability to replicate within host macrophages, resist host immune responses, and ultimately enter a persistent state during a latent tuberculosis infection. Understanding how M. tuberculosis adapts to and replicates in the intracellular environment of the host is crucial for the development of novel, targeted therapeutics. We report the characterization of an M. tuberculosis mutant lacking Rv3249c, a TetR transcriptional regulator. We show that Rv3249c directly represses the adjacent alkB-rubA-rubB operon encoding an alkane hydroxylase/rubredoxin system. For consistency with related systems, we have named the rv3249c gene alkX. The alkX mutant survived better than wild-type M. tuberculosis inside macrophages. This could be phenocopied by overexpression of the alkB-rubA-rubB locus. We hypothesized that the improved intracellular survival phenotype is a result of increased fitness of the mutant; however, we found that the alkX mutant had a defect when grown on some host-associated carbon sources in vitro. We also found that the alkX mutant had a defect in biofilm formation, also linked to the overexpression of the alkB-rubAB genes. Combined, these results define the primary role of AlkX as a transcriptional repressor of the alkB-rubAB operon and suggest the operon contributes to intracellular survival of the pathogen. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the leading cause of death worldwide due to a single infectious agent. It is important to understand how M. tuberculosis adapts to and replicates in the intracellular environment of the host. In this study, we characterized the TetR transcriptional regulator Rv3249c and show that it regulates a highly conserved alkane hydroxylase/rubredoxin system. Our data demonstrate that the AlkBRubAB system contributes to the success of the bacterium in host macrophages.
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影响因子：
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