Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa.
Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa.
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DOI：
10.1128/msystems.00113-22
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发表时间：
2022-04-26
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影响因子：
6.4
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中科院分区：
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在患有囊性纤维化（CF）遗传病的人中，涉及机会性病原体铜绿假单胞菌的细菌感染是发病和死亡的重要原因。铜绿假单胞菌使用称为群体感应 (QS) 的细胞间信号传导机制来调节许多毒力功能。一种类型的 QS 由 LuxI 型信号合酶产生的酰基高丝氨酸内酯 (AHL) 信号组成，该信号结合同源 LuxR 型转录因子。在实验室菌株和条件下，铜绿假单胞菌采用分层排列的两个 AHL 合酶/受体对，其中 LasI/R 系统控制 RhlI/R 系统和许多下游毒力因子。然而，具有 lasR 失活突变的铜绿假单胞菌分离株经常从慢性 CF 感染中分离出来。我们和其他人已经表明，这些分离株经常使用 RhlR 作为主要的 QS 调节因子。 RhlR 在 CF 和环境条件下很少发生突变。我们感兴趣的是确定这些分离株是否具有可重复的遗传特征，以及所有分离株中是否存在受 RhlR 调节的中心基因组。我们检查了 5 个分离株，发现了 CF 分离株共有的适应特征。我们没有找到一个共同的遗传机制来解释从 Las 主导的 QS 到 Rhl 主导的 QS 的转变。我们描述了一个核心 RhlR 调节子，包含编码 7 种产物的 20 个基因。这些结果表明一组关键的 QS 调节因子对于慢性感染的发病机制很重要，并将 RhlR 定位为抗 QS 治疗的靶点。我们的工作强调需要对多种分离株进行采样，以了解超出实验室菌株描述范围的 QS。重要性 细菌病原体铜绿假单胞菌可引起免疫功能低下个体对治疗产生耐药性的慢性感染。在这些感染过程中，最初的感染微生物会适应宿主环境。铜绿假单胞菌使用称为群体感应 (QS) 的细胞间信号传导机制来调节毒力因子和合作行为。实验室菌株中的关键 QS 调节因子 LasR 在适应感染的分离株中经常发生突变，从而使另一个转录因子 RhlR 控制 QS 基因调节。这些分离株提供了一个机会来了解 Rhl-QS 调节，而不会受到 LasR 的混杂影响，以及宿主内进化背景下的 QS 范围。我们发现，在多种感染适应的 LasR 缺失菌株中，一组核心毒力基因受到 RhlR 的调节。我们的结果揭示了感染适应 QS 基因调控和关键 QS 因素的共性，这些因素可能成为未来的治疗靶点。
In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested in determining whether there were reproducible genetic characteristics of these isolates and whether there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las- to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infections and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understand QS beyond what has been described in laboratory strains. IMPORTANCE The bacterial pathogen Pseudomonas aeruginosa can cause chronic infections that are resistant to treatment in immunocompromised individuals. Over the course of these infections, the original infecting organism adapts to the host environment. P. aeruginosa uses a cell-cell signaling mechanism termed quorum sensing (QS) to regulate virulence factors and cooperative behaviors. The key QS regulator in laboratory strains, LasR, is frequently mutated in infection-adapted isolates, leaving another transcription factor, RhlR, in control of QS gene regulation. Such isolates provide an opportunity to understand Rhl-QS regulation without the confounding effects of LasR, as well as the scope of QS in the context of within-host evolution. We show that a core group of virulence genes is regulated by RhlR in a variety of infection-adapted LasR-null isolates. Our results reveal commonalities in infection-adapted QS gene regulation and key QS factors that may serve as therapeutic targets in the future.
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影响因子：
14.9
作者：
Chen IA;Chu K;Palaniappan K;Pillay M;Ratner A;Huang J;Huntemann M;Varghese N;White JR;Seshadri R;Smirnova T;Kirton E;Jungbluth SP;Woyke T;Eloe-Fadrosh EA;Ivanova NN;Kyrpides NC
通讯作者：
Kyrpides NC
影响因子：
14.8
作者：
Hmelo LR;Borlee BR;Almblad H;Love ME;Randall TE;Tseng BS;Lin C;Irie Y;Storek KM;Yang JJ;Siehnel RJ;Howell PL;Singh PK;Tolker-Nielsen T;Parsek MR;Schweizer HP;Harrison JJ
通讯作者：
Harrison JJ
影响因子：
1.7
作者：
Bankevich, Anton;Nurk, Sergey;Pevzner, Pavel A.
通讯作者：
Pevzner, Pavel A.
DOI：
10.1073/pnas.051624298
发表时间：
2001-02-27
影响因子：
11.1
作者：
Chugani, SA;Whiteley, M;Greenberg, EP
通讯作者：
Greenberg, EP
DOI：
10.1073/pnas.0307694100
发表时间：
2004-02-03
影响因子：
11.1
作者：
Déziel, E;Lépine, F;Rahme, LG
通讯作者：
Rahme, LG