A novel signal transduction pathway that modulates rhl quorum sensing and bacterial virulence in Pseudomonas aeruginosa.
A novel signal transduction pathway that modulates rhl quorum sensing and bacterial virulence in Pseudomonas aeruginosa.
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DOI：
10.1371/journal.ppat.1004340
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发表时间：
2014-08
期刊：
影响因子：
6.7
通讯作者：
Lan L
中科院分区：
文献类型：
--
作者：
Cao Q;Wang Y;Chen F;Xia Y;Lou J;Zhang X;Yang N;Sun X;Zhang Q;Zhuo C;Huang X;Deng X;Yang CG;Ye Y;Zhao J;Wu M;Lan L
rhl 群体感应 (QS) 系统在铜绿假单胞菌的发病机制中发挥着关键作用。然而，人们对 rhl QS 系统直接上游的调节作用知之甚少。在这里，我们发现，编码二元传感器 BfmS 的基因缺失会导致其同源响应调节因子 BfmR 的激活，BfmR 反过来直接与启动子结合，并降低编码 QS 调节因子 RhlR 的 rhlR 基因的表达，从而抑制 rhl QS 系统。在 bfmS 缺失的情况下，Acka-Pta 途径可以调节 BfmR 的调节活性。此外，BfmS 还可以调节 202 个基因的表达，这些基因占铜绿假单胞菌基因组的 3.6%。我们进一步证明，bfmS 的缺失会导致生菜叶中的毒力大幅降低、细胞毒性降低、侵袭增强以及小鼠急性肺部感染期间细菌存活率降低。有趣的是，在铜绿假单胞菌囊性纤维化 (CF) 分离株（如 DK2 菌株和 RP73 菌株）的 bfmS 基因中自然发生的特定错义突变可以产生 BfmS 变体（BfmSL181P、BfmSL181P/E376Q 和 BfmSR393H），这些变体不再抑制 BfmR，而是激活 BfmR。因此，BfmS 变体（而非野生型 BfmS）抑制 rhl QS 系统。因此，这项研究揭示了一条先前未探索的信号转导途径，BfmS/BfmR/RhlR，用于调节铜绿假单胞菌中的 rhl QS。我们认为，BfmRS TCS 可能在 CF 肺部慢性感染期间铜绿假单胞菌毒力的调节和进化中发挥重要作用。 rhl 群体感应 (QS) 系统使铜绿假单胞菌能够调节多种代谢适应和毒力。然而，rhl QS 系统是如何调节的仍然很大程度上未知。在这里，我们报道了二元传感器BfmS通过抑制其同源反应调节因子BfmR来控制rhl QS系统，BfmR直接抑制rhl QS调节因子RhlR基因的表达并减少QS信号分子N-丁酰基-L-高丝氨酸内酯（C4-HSL）的产生。我们发现 BfmS 对于铜绿假单胞菌调节毒力相关性状表达和适应宿主的能力至关重要。有趣的是，虽然野生型 BfmS 是 BfmR 的阻遏蛋白，但天然发生的错义突变（L181P、L181P/E376Q 或 R393H）可以将其功能从 BfmR 阻遏蛋白转变为 BfmR 激活蛋白，导致 BfmR 激活，进而降低 rhl QS 信号 C4-HSL 的水平。因此，这些结果为铜绿假单胞菌毒力的调节和进化提供了重要且新颖的见解。
The rhl quorum-sensing (QS) system plays critical roles in the pathogenesis of P. aeruginosa. However, the regulatory effects that occur directly upstream of the rhl QS system are poorly understood. Here, we show that deletion of gene encoding for the two-component sensor BfmS leads to the activation of its cognate response regulator BfmR, which in turn directly binds to the promoter and decreases the expression of the rhlR gene that encodes the QS regulator RhlR, causing the inhibition of the rhl QS system. In the absence of bfmS, the Acka-Pta pathway can modulate the regulatory activity of BfmR. In addition, BfmS tunes the expression of 202 genes that comprise 3.6% of the P. aeruginosa genome. We further demonstrate that deletion of bfmS causes substantially reduced virulence in lettuce leaf, reduced cytotoxicity, enhanced invasion, and reduced bacterial survival during acute mouse lung infection. Intriguingly, specific missense mutations, which occur naturally in the bfmS gene in P. aeruginosa cystic fibrosis (CF) isolates such as DK2 strains and RP73 strain, can produce BfmS variants (BfmSL181P, BfmSL181P/E376Q, and BfmSR393H) that no longer repress, but instead activate BfmR. As a result, BfmS variants, but not the wild-type BfmS, inhibit the rhl QS system. This study thus uncovers a previously unexplored signal transduction pathway, BfmS/BfmR/RhlR, for the regulation of rhl QS in P. aeruginosa. We propose that BfmRS TCS may have an important role in the regulation and evolution of P. aeruginosa virulence during chronic infection in CF lungs. The rhl quorum-sensing (QS) system allows P. aeruginosa to regulate diverse metabolic adaptations and virulence. However, how rhl QS system is regulated remains largely unknown. Here, we report that two-component sensor BfmS controls rhl QS system by repressing its cognate response regulator BfmR, which directly suppresses the expression of rhl QS regulator RhlR gene and reduces the production of QS signal molecule N-butanoyl-L-homoserine lactone (C4-HSL). We find that BfmS is critical to the ability of P. aeruginosa to modulate the expression of virulence-associated traits and adapt to the host. Intriguingly, although wild-type BfmS is a repressor of BfmR, naturally occurring missense mutation (L181P, L181P/E376Q, or R393H) can convert its function from a repressor to an activator of BfmR, leading to BfmR activation, which in turn reduces the level of rhl QS signal C4-HSL. These results, therefore, provide important and novel insight into the regulation and evolution of P. aeruginosa virulence.
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影响因子：
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作者：
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通讯作者：
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