Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.
Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Mol Microbiol. 2022 May;117(5):1048-1062. doi: 10.1111/mmi.14886. Epub 2022 Feb 28.
For Mycobacterium tuberculosis (Mtb) to successfully infect a host, it must be able to adapt to changes in its microenvironment, including variations in ionic signals such as pH and chloride (Cl ), and link these responses to its growth. Transcriptional changes are a key mechanism for Mtb environmental adaptation, and we identify here Rv0500A as a novel transcriptional regulator that links Mtb environmental response and division processes. Global transcriptional profiling revealed that Rv0500A acts as a repressor and influences the expression of genes related to division, with the magnitude of its effect modulated by pH and Cl . Rv0500A can directly bind the promoters of several of these target genes, and we identify key residues required for its DNA-binding ability and biological effect. Overexpression of rv0500A disrupted Mtb growth morphology, resulting in filamentation that was exacerbated by high environmental Cl levels and acidic pH. Finally, we show that perturbation of rv0500A leads to attenuation of the ability of Mtb to colonize its host in vivo. Our work highlights the important link between Mtb environmental response and growth characteristics, and uncovers a new transcription factor involved in this critical facet of Mtb biology.
为了成功感染宿主，结核分枝杆菌（Mtb）必须能够适应其微环境的变化，包括 pH 值和氯离子（Cl ）等离子信号的变化，并将这些反应与其生长联系起来。转录变化是 Mtb 环境适应的关键机制，我们在这里确定 Rv0500A 是一种新型的转录调节因子，它将 Mtb 环境反应和分裂过程联系起来。全基因组转录谱分析显示，Rv0500A 作为一种阻遏物发挥作用，影响与分裂相关的基因表达，其影响幅度受 pH 值和 Cl 调节。Rv0500A 可以直接结合这些靶基因的启动子，我们确定了其 DNA 结合能力和生物学效应所必需的关键残基。rv0500A 的过表达破坏了 Mtb 的生长形态，导致丝状化，而高环境 Cl 水平和酸性 pH 会加剧这种现象。最后，我们表明 rv0500A 的扰动导致 Mtb 在体内定植宿主的能力减弱。我们的工作强调了 Mtb 环境反应与生长特性之间的重要联系，并揭示了一种参与 Mtb 生物学这一关键方面的新转录因子。
