The Global Regulator MftR Controls Virulence and Siderophore Production in Burkholderia thailandensis
The Global Regulator MftR Controls Virulence and Siderophore Production in Burkholderia thailandensis
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DOI：
10.1128/jb.00237-22
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发表时间：
2022-10
影响因子：
3.2
通讯作者：
S. Thapa;A. Al-Tohamy;A. Grove
中科院分区：
文献类型：
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作者：
S. Thapa;A. Al-Tohamy;A. Grove
细菌病原体在宿主环境中面临铁的限制。为了克服这一挑战，它们产生了铁载体，一种小的铁螯合分子。泰国伯克霍尔德菌是假马利氏伯克霍尔德菌复合体的一员。它编码转录因子MftR，该转录因子在致病性较强的伯克霍尔德氏菌中是保守的，并且先前被证明是基因表达的全球调节剂。我们在这里报道了mftR基因被破坏的泰国芽孢杆菌菌株在秀丽隐杆线虫和洋葱中都具有更强的毒力。ΔmftR菌株表现出许多与毒力相关的表型。它更擅长形成生物膜，而与生物膜内厌氧生存和适应性有关的arcDABC基因簇被上调。ΔmftR细胞的游泳和群体运动能力也有所提高。我们进一步表明MftR是控制铁载体malleobactin产生的几个转录因子之一。MftR直接结合到驱动mba表达的启动子上，该启动子编码细胞外质功能sigma因子mba，这是malleobactin产生所必需的。Malleobactin是泰国芽孢杆菌的主要铁载体，其证据是mbaS::Tc细胞中铁载体的产生减少，其中mbaS被破坏。在ΔmftR细胞中，mba的表达增加了5倍，铁载体的产生也增加了。在限铁条件下，野生型和ΔmftR细胞的mba表达分别增加了约150倍，反映了铁摄取调节剂（Fur）的调节。mba的表达谱也指出了一种独立的配体反应转录因子（可能是ScmR）的抑制作用。综上所述，这些数据表明MftR控制着许多表型，所有这些表型都促进了细菌在宿主环境中的生存。细菌病原体在宿主环境中面临铁限制。为了克服这一挑战，它们产生了铁载体，一种小的铁螯合分子。铁-铁载体复合物的吸收避免了细菌对铁的限制。在伯克霍尔德氏菌中，马利杆菌蛋白或相关化合物是主要的铁载体。我们在这里表明，泰国芽孢杆菌生产马来菌素所需的蛋白质编码基因受到全局转录因子MftR的直接控制。当MftR结合宿主细胞中的嘌呤代谢物黄嘌呤时，MftR对基因表达的抑制得以缓解。因此，我们的工作确定了一种机制，通过这种机制，铁载体的生产可能在宿主环境中得到优化，从而有助于细菌的适应性。
Bacterial pathogens face iron limitation in a host environment. To overcome this challenge, they produce siderophores, small iron-chelating molecules. ABSTRACT Burkholderia thailandensis is a member of the Burkholderia pseudomallei complex. It encodes the transcription factor MftR, which is conserved among the more pathogenic Burkholderia spp. and previously shown to be a global regulator of gene expression. We report here that a B. thailandensis strain in which the mftR gene is disrupted is more virulent in both Caenorhabditis elegans and onion. The ΔmftR strain exhibits a number of phenotypes associated with virulence. It is more proficient at forming biofilm, and the arcDABC gene cluster, which has been linked to anaerobic survival and fitness within a biofilm, is upregulated. Swimming and swarming motility are also elevated in ΔmftR cells. We further show that MftR is one of several transcription factors which control production of the siderophore malleobactin. MftR binds directly to the promoter driving expression of mbaS, which encodes the extracytoplasmic function sigma factor MbaS that is required for malleobactin production. Malleobactin is a primary siderophore in B. thailandensis as evidenced by reduced siderophore production in mbaS::Tc cells, in which mbaS is disrupted. Expression of mbaS is increased ~5-fold in ΔmftR cells, and siderophore production is elevated. Under iron-limiting conditions, mbaS expression is increased ~150-fold in both wild-type and ΔmftR cells, respectively, reflecting regulation by the ferric uptake regulator (Fur). The mbaS expression profiles also point to repression by a separate, ligand-responsive transcription factor, possibly ScmR. Taken together, these data indicate that MftR controls a number of phenotypes, all of which promote bacterial survival in a host environment. IMPORTANCE Bacterial pathogens face iron limitation in a host environment. To overcome this challenge, they produce siderophores, small iron-chelating molecules. Uptake of iron-siderophore complexes averts bacterial iron limitation. In Burkholderia spp., malleobactin or related compounds are the primary siderophores. We show here that genes encoding proteins required for malleobactin production in B. thailandensis are under the direct control of the global transcription factor MftR. Repression of gene expression by MftR is relieved when MftR binds xanthine, a purine metabolite present in host cells. Our work therefore identifies a mechanism by which siderophore production may be optimized in a host environment, thus contributing to bacterial fitness.