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: 10797300
• 负责人: Jon E Paczkowski
• 金额: $ 15.45万
• 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/10797300
• 关键词: Architecture; Bacteria; Behavior; Binding; Cell Communication; Cell Density; Cell Signaling Process; Cells; Clinical; Communication; Communities; Complex; Detection; Development; Down-Regulation; Gene Expression; Gene Expression Profile; Genes; Infection; Ligands; Light; Mediating; Medicine; Microbial Biofilms; Mutation; Nucleic Acids; Organism; Output; Pathogenesis; Phase; Play; Production; Proteins; Pseudomonas aeruginosa; Regulation; Regulatory Element; Relaxation; 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; rhamnolipid; surfactant

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. The progression into QS corresponds to a downregulation of certain regulatory elements that function at low cell density to potentially mitigate early entry into QS. We have discovered that Fis, which is expressed during log phase, regulates the production of rhlA, a gene responsible for the synthesis of rhamnolipids, which are a bacterial surfactant important for infections. We will explore the mechanism Fis uses to achieve this regulation, in addition to what role it might play in regulating other QS genes and behaviors in AIM 2. The acquisition of the Malvern Panalytical MicroCal PEAQ ITC will elucidate the different mechanisms that underpin quorum sensing progression as they relate to protein-protein, protein-nucleic acid, and protein-ligand interactions.

项目总结

项目成果

Quorum-sensing synthase mutations re-calibrate autoinducer concentrations in clinical isolates of Pseudomonas aeruginosa to enhance pathogenesis.

群体感应合酶突变重新校准铜绿假单胞菌临床分离株中的自诱导剂浓度，以增强发病机制。

• DOI: 10.1038/s41467-023-43702-4
• 发表时间: 2023-12-02
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Simanek, Kayla A.;Schumacher, Megan L.;Mallery, Caleb P.;Shen, Stella;Li, Lingyun;Paczkowski, Jon E.
• 通讯作者: Paczkowski, Jon E.

Structure of the RhlR-PqsE complex from Pseudomonas aeruginosa reveals mechanistic insights into quorum-sensing gene regulation.

• DOI: 10.1016/j.str.2022.10.008
• 发表时间: 2022-12-01
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Feathers, J. Ryan;Richael, Erica K.;Simanek, Kayla A.;Fromme, J. Christopher;Paczkowski, Jon E.
• 通讯作者: Paczkowski, Jon E.

Resistance Is Not Futile: The Role of Quorum Sensing Plasticity in Pseudomonas aeruginosa Infections and Its Link to Intrinsic Mechanisms of Antibiotic Resistance.

抗性并非徒劳：群体感应可塑性在铜绿假单胞菌感染中的作用及其与抗生素耐药性内在机制的联系。

• DOI: 10.3390/microorganisms10061247
• 发表时间: 2022-06-18
• 期刊: Microorganisms
• 影响因子: 4.5