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: 10597249
• 负责人: George A. O'Toole
• 金额: $ 38.63万
• 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/10597249
• 关键词: Adhesions; Architecture; Bacteria; Bacterial Adhesins; Bacterial Genome; Binding; Biochemical; Bioinformatics; Cell Adhesion; Cell surface; Citrates; Communicable Diseases; Complex; Conserved Sequence; Cytoplasm; Desulfovibrio vulgaris; Development; Dinucleoside Phosphates; Family; Family member; Genetic; Homologous Gene; Human; Intestines; Life Style; Ligand Binding; Ligand Binding Domain; 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; analog; chronic infection; diguanylate cyclase; extracellular; gut microbiota; host-microbe interactions; insight; microbial community; novel; novel therapeutics; pathogenic bacteria; pathogenic microbe; periplasm; posttranscriptional; 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： 我们研究从环境输入到生理输入的分子机制和信号传导 输出，控制细菌生物膜的形成，这是与宿主微生物相关的关键细菌生活方式 特别是细菌的感知和反应能力。 适应各种微环境，特别是在从自由游泳到自由游泳的过渡期间 固着生物膜的生活方式，有助于慢性感染的形成。 对于可以共生的非致病性细菌来说，机制同样重要 与其宿主的关系。了解信号传导的架构和调节。 控制细菌细胞粘附和生物膜形成的系统在开发中至关重要 新疗法和预防性干预措施，同时提供基本见解 在这里，我们提出了对广泛保守的机制研究。 细胞粘附系统对于多种致病性和生物膜形成至关重要 我们将重点关注有关如何共生的基本未解答的问题。 环二 GMP 网络控制这些粘附素的定位以及两个这样的粘附素如何 我们还将通过以下方式增强我们研究的影响。 研究在重要的共生硫酸盐中新发现的类似信号系统 该提案的中心假设是环二 GMP 信号传导。 通过配体响应性 DGC 网络调节多个生物膜的形成 在致病、宿主相关和环境中具有重要作用的微生物。 提出以下具体目标来检验这一假设： 目的 1. 检验小分子配体对于调节局部化至关重要的假设 cdG 网络通过荧光假单胞菌中的受体复合物。 目的 2. 检验 Pfl 中 LapA 和 MapA 的离散域结构贡献的假设 其对生物膜形成的不同影响。 AIM 3.检验硫酸盐还原菌LapD/LapG样系统的假设 控制这种肠道细菌 LapA 同源物的定位。