Characterization of the mechanisms underpinning quorum sensing progression in Pseudomonas aeruginosa

铜绿假单胞菌群体感应进展机制的表征

• 批准号: 10642512
• 负责人: Jon E Paczkowski
• 金额: $ 4.01万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642512
• 关键词: Architecture; Bacteria; Behavior; Binding; Cell Communication; Cell Signaling Process; Cells; Clinical; Communication; Communities; Complex; Detection; Development; Gene Expression; Gene Expression Profile; Genes; Hydrolase; Ligands; Light; Mediating; Medicine; Microbial Biofilms; Mutation; Organism; Output; Pathogenesis; Play; Production; Pseudomonas aeruginosa; Role; Shapes; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; System; Transcriptional Regulation; Virulence; combat; extracellular; insight; microbial community; pathogenic bacteria; quorum sensing; receptor; receptor binding; response

PROJECT SUMMARY Quorum sensing (QS) is a mechanism of cell-cell communication that bacteria use to orchestrate collective behaviors, including virulence and biofilm formation. QS relies on the production, release, and group- wide detection of extracellular signal molecules called autoinducers (AI). QS allows bacteria to synchronously alter gene expression patterns that underpin collective behaviors, for example, biofilm formation. Some receptors bind and respond exclusively to one AI, while others bind and respond to multiple AIs. QS is responsible for releasing public goods that are beneficial to kin and, potentially, non-kin, and as a result, it plays an important role in shaping microbial community architecture. QS is now understood to be the norm in the bacterial world. Nonetheless, how different bacterial QS receptors initiate signal transduction is not understood. Defining the mechanisms that regulate QS-mediated production of public goods will be key for generally understanding how organisms coordinate community level changes in gene expression. This is particularly important in light of our findings that P. aeruginosa QS can be activated by signals produced by non-kin. Thus, determining the mechanisms that regulate QS progression after signal recognition will allow us to understand the respective benefits and drawbacks of strict versus relaxed ligand detection in QS-mediated communication. Bacteria live in heterogeneous communities and encounter mixtures of AIs produced by themselves, their kin, and their non-kin neighbors. Upon signal recognition, LasR and RhlR activate hundreds of genes, many of which are involved in pathogenesis and biofilm formation. While some signal transduction pathways follow a linear circuit, the QS system in P. aeruginosa is best described as a dense network of receptors and regulators with interconnecting regulatory systems and outputs. Canonically, the LasR-AI complex activates expression of rhlR and rhlI, thus launching the second QS system, enabling the two QS systems to function in tandem. Surprisingly, rhlR can be upregulated in clinical isolates containing lasR inactivating mutations. RhlR can also function without its partner synthase to regulate certain genes. This is achieved via a metallo-hydrolase known as PqsE. We discovered that PqsE and RhlR interact to form a complex. We will explore the role of PqsE in regulating RhlR function and describe their tandem role in transcriptional regulation and pathogenesis in AIM 1.

项目摘要 群体感应（Quorum sensing，QS）是细菌用来协调细胞间通讯的机制 集体行为，包括毒力和生物膜形成。QS依赖于生产、发布和集团- 广泛检测细胞外信号分子称为自诱导物（AI）。QS允许细菌同步 改变支持集体行为的基因表达模式，例如生物膜形成。一些受体 绑定并只响应一个AI，而其他AI绑定并响应多个AI。QS负责 释放对亲属和潜在的非亲属有益的公共产品，因此，它发挥了重要的作用， 在塑造微生物群落结构中的作用。QS现在被认为是细菌世界的标准。 然而，不同的细菌QS受体如何启动信号转导尚不清楚。定义 规范以质量服务为中介的公共产品生产的机制将是普遍理解如何实现这一目标的关键。 生物体协调基因表达的群落水平变化。鉴于我们的情况，这一点尤其重要 发现铜绿假单胞菌QS可以被非亲属产生的信号激活。因此，确定 在信号识别后调节QS进展的机制将使我们能够理解 在QS介导的通讯中严格与宽松配体检测的优缺点。细菌生活在 异质社区，并遇到由他们自己，他们的亲属和他们的非亲属产生的AI的混合物 邻居在信号识别后，LasR和RhlR激活数百个基因，其中许多基因参与了信号转导。 发病机制和生物膜形成。虽然一些信号转导途径遵循线性电路，但QS 铜绿假单胞菌中的系统最好描述为受体和调节剂的密集网络， 监管制度和产出。典型地，LasR-AI复合物激活rhlR和rhlI的表达，因此 启动第二个QS系统，使两个QS系统协同工作。令人惊讶的是，rhlR可以 在含有lasR失活突变的临床分离株中上调。RhlR也可以在没有伴侣的情况下发挥作用 合成酶来调节某些基因。这是通过称为PqsE的金属水解酶实现的。我们发现 PqsE和RhlR相互作用形成复合物。我们将探讨PqsE在调节RhlR功能中的作用， 描述了它们在AIM 1转录调控和发病机制中的串联作用。