cdG Signaling and Adhesion Deployment During Biofilm Initiation

生物膜启动期间的 cdG 信号传导和粘附部署

• 批准号: 10417364
• 负责人: George A. O'Toole
• 金额: $ 40.23万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417364
• 关键词: Adhesions; Architecture; Bacteria; Bacterial Adhesins; Bacterial Genome; Binding; Biochemical; Bioinformatics; Cell Adhesion; Cell surface; Citrates; Communicable Diseases; Complex; Crete; Desulfovibrio vulgaris; Development; Dinucleoside Phosphates; Family; Family member; Genetic; Genetic Transcription; Homologous Gene; Human; Intestines; Life Style; Ligand Binding; Ligands; Link; Mediating; Membrane; Microbe; Microbial Biofilms; Molecular; Organism; Output; Pathogenicity; Peptide Hydrolases; Periodicity; Phylogenetic Analysis; Physiological; Polysaccharides; Process; Production; Proteins; Pseudomonas fluorescens; Regulation; Reporting; Role; Second Messenger Systems; Signal Transduction; Structure; Surface; Swimming; System; Testing; Variant; Work; adhesion receptor; analog; chronic infection; diguanylate cyclase; extracellular; gut microbiota; host-microbe interactions; insight; microbial community; novel; novel therapeutics; pathogenic bacteria; pathogenic microbe; periplasm; preventive intervention; receptor; reconstitution; response; small molecule; sugar; sulfate reducing bacteria; tool

Abstract: We study the molecular mechanisms and signaling, from environmental input to physiological output, that control bacterial biofilm formation, a key bacterial lifestyle linked to host-microbe interactions and infectious disease. In particular, the capability of bacteria to sense and respond to various microenvironments, particularly during the transition from a free-swimming to a sessile biofilm lifestyle, contributes to the establishment of chronic infections. The underlying mechanisms are equally important for non-pathogenic bacteria that can live in commensal relationship with their host(s). Understanding the architecture and regulation of signaling systems that control bacterial cell adhesion and biofilm formation is critical in the development of novel therapies and preventative interventions, while providing fundamental insight into bacterial signaling processes. Here, we propose mechanistic studies on a broadly conserved cell adhesion system that is crucial for biofilm formation in a variety of pathogenic and commensal organisms. We will focus on fundamental unanswered questions concerning how cyclic-di-GMP networks control localization of these adhesins as well as how two such adhesins contribute to formation of biofilms. We will also enhance the impact of our studies by investigating a newly identified, analogous signaling system in an important commensal sulfate- reducing bacterium. The central hypothesis of this proposal is that cyclic-di-GMP signaling via a network of ligand-responsive DGCs regulates biofilm formation across a number of microbes of importance in pathogenic, host-associated, and environmental contexts. We propose the following Specific Aims to test this hypothesis: AIM 1. Test the hypothesis that small-molecule ligands are critical for regulating the localized cdG network via receptor complexes in P. fluorescens. AIM 2. Test the hypothesis that discrete domain structures of LapA and MapA in Pfl contribute to their differential impacts on biofilm formation. AIM 3. Test the hypothesis that the sulfate-reducing bacterium LapD/LapG-like system controls localization of this intestinal bacterium’s LapA homolog.

抽象的： 我们研究了从环境输入到生理的分子机制和信号传导 输出，控制细菌的生物膜形成，一种与宿主微叶相关的关键细菌生活方式 相互作用和传染病。特别是，细菌感知和反应的能力 到各种微环境，尤其是在从自由游动到一个的过渡期间 无柄生物膜的生活方式有助于建立慢性感染。基础 机制对于可以生活在共生中的非致病细菌同样重要 与他们的主人的关系。了解信号的结构和调节 控制细菌细胞粘合剂和生物膜形成的系统在发育中至关重要 新型疗法和预防性干预措施，同时提供基本的见解 细菌信号传导过程。在这里，我们提出了关于广泛保守的机械研究 细胞粘合剂系统对于多种致病性和 共生生物。我们将重点介绍有关如何的基本未解决问题 循环-DI-GMP网络控制这些粘合剂的定位以及两种此类粘合剂如何 有助于生物膜的形成。我们还将通过 研究重要的共同硫酸盐 - 还原细菌。该提议的中心假设是环状-DI-GMP信号传导 通过配体响应DGC网络调节许多跨多个生物膜形成 在致病，相关和环境环境中重要的微生物。我们 建议以下具体旨在检验这一假设的特定目的： 目的1。检验假设，即小分子配体对于调节局部化至关重要 CDG网络通过荧光假单胞菌中的接收器复合物。 目标2。检验以下假设：PFL中LAPA和MAPA的离散域结构有助于 它们对生物膜形成的不同影响。 AIM 3。检验以下假设：还原硫酸盐的细菌LAPD/LAPG样系统 控制这种肠道细菌LAPA同源物的定位。