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.

摘要： 我们研究了从环境输入到生理信号的分子机制和信号传导， 输出，控制细菌生物膜的形成，一个关键的细菌生活方式与宿主微生物 相互作用和传染病。特别是细菌感知和反应的能力 各种微环境，特别是在从自由游泳过渡到 固着生物膜的生活方式，有助于建立慢性感染。底层 对于可以在肠道中生存的非致病性细菌， 与宿主的关系。了解信号的结构和调节 控制细菌细胞粘附和生物膜形成的系统在发展中至关重要 新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，我们提出了一个广泛保守的机制研究 细胞粘附系统，这是至关重要的生物膜的形成，在各种致病性和 浮游生物。我们将集中在基本的未回答的问题， 环状二GMP网络控制这些粘附素的定位以及两种这样的粘附素如何 有助于形成生物膜。我们亦会透过以下措施，加强研究的影响力： 研究一个新发现的，类似的信号系统，在一个重要的硫酸镁， 还原菌该建议的中心假设是， 通过配体响应性DGC网络调节生物膜的形成， 微生物的重要性，在病原体，主机相关，和环境背景。我们 提出以下具体目标来检验这一假设： AIM 1.测试小分子配体对于调节局部化的 cdG网络通过受体复合物在荧光假单胞菌。 AIM 2.检验Pfl中LapA和MapA的离散结构域结构有助于 它们对生物膜形成的不同影响。 AIM 3.验证硫酸盐还原菌LapD/LapG样系统 控制这种肠道细菌的LapA同源物的定位。