cdG Signaling and Adhesion Deployment During Biofilm Initiation

摘要： 我们研究了从环境输入到生理输入的分子机制和信号转导 输出，控制细菌生物膜的形成，这是与宿主微生物联系在一起的关键细菌生活方式 相互作用和传染病。尤其是细菌感知和反应的能力 不同的微环境，特别是在从自由泳向自由泳过渡的过程中 固着生物膜的生活方式，有助于建立慢性感染。潜在的 对于可以共生的非致病细菌来说，机制同样重要 与东道主(S)的关系。了解信令的体系结构和规则 控制细菌细胞黏附和生物膜形成的系统在开发中至关重要 新的治疗方法和预防性干预，同时提供对 细菌的信号传递过程。在这里，我们建议对一个广泛守恒的 细胞黏附系统在多种致病和致病的细菌生物膜形成中起关键作用 共生生物。我们将专注于尚未回答的基本问题，即如何 环-双-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 有助于生物膜的形成。我们还会通过以下方式加强研究的影响 在一个重要的共生硫酸盐中研究新发现的类似信号系统- 减少细菌。这一提议的中心假设是，周期-二-GMP信号 通过配体反应的DGC网络调节许多生物膜的形成 病原微生物、寄主相关微生物和环境微生物。我们 提出以下具体目标来检验这一假设： 目的1.验证小分子配体对调节局域化的 荧光假单胞菌通过受体复合体形成CDG网络。 目的2.检验PFL中LAPA和MAPA的离散结构域结构对PFL贡献的假设 它们对生物膜形成的不同影响。 目的3.验证硫酸盐还原细菌LapG/LapG系统的假说 控制这种肠道细菌的LapA同源物的定位。

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.