Control of Klebsiella capsule biosynthesis and attachment

克雷伯菌荚膜生物合成和附着的控制

• 批准号: 10713888
• 负责人: Laura Anzaldi Mike
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713888
• 关键词: Adherence; Amoeba genus; Anabolism; Area; Bacteria; Bacteriophages; Cell surface; Cells; Complex; Dehydration; Endogenous Factors; Environment; Environmental Protection; Epithelial Cells; Escherichia coli; Exogenous Factors; Foundations; Gastrointestinal tract structure; Genes; Genetic; Goals; Gram-Negative Bacteria; Heterogeneity; Human; Immune Evasion; Intervention; Klebsiella; Laboratories; Membrane; Metabolic; Metabolism; Microbial Biofilms; Modeling; Nutrient; Polysaccharides; Population; Predatory Behavior; Predisposition; Process; Production; Research; Sewage; Shapes; Signal Transduction; Soil; Source; Surface; Vision; bacterial fitness; capsule; environmental change; environmental stressor; extracellular; fitness; flexibility; gut bacteria; gut colonization; pressure; programs; response; ultraviolet irradiation

SUMMARY Capsular polysaccharide (CPS) is the outermost barrier between bacteria and their environment. It shapes bacterial interactions with external factors, including adherence to surfaces (e.g. biofilm formation, epithelial cell association); protection from environmental stressors (e.g., dehydration, UV irradiation); susceptibility to predation (e.g., phage, bacteria, or amoeba); or immune evasion (e.g. opsonophagocytosis). The Klebsiella species complex is comprised of non-fastidious Gram-negative bacteria that colonize diverse environments, including soil, sewage, sink drains, and mammalian guts. Klebsiella are early colonizers of the human gastrointestinal tract and, when environmental conditions shift in the gut, they have the potential to bloom and out-compete all other colonizers, including closely related Enterobacterales such as E. coli. Clearly, Klebsiella metabolic capacity is robust and flexible. Moreover, Klebsiella CPS production is required for efficient gut colonization and persistence. There is a major gap in our understanding of how exogenous signals are transduced through Klebsiella metabolism and intracellular regulatory networks to control CPS production and how that CPS is attached to the outer envelope. Our long-term goal is to understand how bacterial control of CPS biosynthesis and attachment shapes fitness in response to changing environmental pressures at both single cell and population levels. The objective of this application is to establish a model of the exogenous and endogenous factors that control Klebsiella CPS biosynthesis and cell surface attachment. We seek to establish a framework for understanding how Klebsiella and other Gram- negative bacteria integrate exogenous nutrient signals with their metabolic and regulatory networks to hone their fitness under varying environmental pressures. Recent progress in the laboratory has identified specific genes and some environmental signals that alter CPS attachment and abundance. Our proposed project areas are to examine (1) the mechanisms controlling CPS attachment and release at the outer membrane and (2) how external nutrient sources and cellular metabolism regulate CPS biosynthesis. The overall vision of our research program is to develop a model of how extracellular signals combined with genetic and regulatory heterogeneity create dynamic surface exposed glycans within a bacterial population to enhance overall fitness in the face of environmental challenges. This will provide the foundation for identifying potential intervention points that could be targeted to modulate bacterial CPS production and decolonize specific niches.

概括 荚膜多糖（CPS）是细菌与其环境之间的最外层屏障。它 塑造细菌与外部因素的相互作用，包括对表面的粘附（例如生物膜 形成，上皮细胞结合）；免受环境压力（例如脱水、紫外线 辐照）；对捕食的敏感性（例如噬菌体、细菌或阿米巴原虫）；或免疫逃避（例如 调理吞噬作用）。克雷伯菌属复合体由不挑剔的革兰氏阴性菌组成 定植于不同环境的细菌，包括土壤、污水、水槽排水沟和哺乳动物肠道。 克雷伯氏菌是人类胃肠道的早期定殖者，当环境条件 随着肠道的转变，它们有潜力蓬勃发展并超越所有其他殖民者，包括密切关注的 相关肠杆菌，例如大肠杆菌。显然，克雷伯氏菌的代谢能力强大且灵活。 此外，克雷伯氏菌 CPS 的产生是有效肠道定植和持久性所必需的。有 我们对外源信号如何通过克雷伯氏菌转导的理解存在重大差距 代谢和细胞内调节网络控制 CPS 的产生以及 CPS 的产生方式 附在外信封上。我们的长期目标是了解细菌如何控制 CPS 生物合成和附着塑造适应性，以应对不断变化的环境压力 单细胞和群体水平。该应用程序的目的是建立一个模型 控制克雷伯菌 CPS 生物合成和细胞表面的外源和内源因素 依恋。我们寻求建立一个框架来理解克雷伯菌和其他革兰氏菌如何 阴性细菌将外源营养信号与其代谢和调节网络整合起来 在不同的环境压力下磨练他们的健康。实验室最新进展 确定了改变 CPS 附着和丰度的特定基因和一些环境信号。 我们提议的项目领域是检查 (1) 控制 CPS 附着的机制和 外膜释放以及（2）外部营养源和细胞代谢如何调节 CPS生物合成。我们研究项目的总体愿景是开发一个模型来解释细胞外如何 信号与遗传和调控异质性相结合，产生动态的表面暴露聚糖 在细菌种群中增强整体适应能力以应对环境挑战。这将 为确定可针对性调节的潜在干预点提供基础 细菌 CPS 的产生和去定殖特定的生态位。