Control of Klebsiella capsule biosynthesis and attachment

摘要 荚膜多糖(CPS)是细菌与环境之间最外层的屏障。它 塑造细菌与外部因素的相互作用，包括附着在表面(例如生物膜 形成、上皮细胞联合)；防止环境应激源(例如，脱水、紫外线 辐射)；对捕食的敏感性(例如，噬菌体、细菌或阿米巴)；或免疫逃避(例如 吞噬细胞增多症)。克雷伯氏菌的物种复合体由非挑剔的革兰氏阴性菌组成 寄生在不同环境中的细菌，包括土壤、污水、下水道和哺乳动物的肠道。 克雷伯氏菌是人类胃肠道的早期定殖者，当环境条件 在胆量发生变化的情况下，它们有潜力蓬勃发展并击败所有其他殖民者，包括势均力敌的殖民者 相关的肠杆菌属，如大肠杆菌。显然，克雷伯氏菌的代谢能力是强大和灵活的。 此外，克雷伯氏菌CPS的生产是有效的肠道定植和持久性所必需的。的确有 我们对外源信号是如何通过克雷伯氏菌转导的理解上的一个主要差距 控制CPS产生的新陈代谢和细胞内调节网络以及CPS是如何产生的 贴在外面的信封上。我们的长期目标是了解CPS的细菌控制 生物合成和依恋形成适应能力，以响应环境压力的变化 单细胞水平和群体水平。这个应用程序的目标是建立一个 控制克雷伯氏菌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，以了解克雷伯氏菌和其他革兰氏菌是如何- 负性细菌将外源营养信号与其代谢和调节网络相结合，以 在不同的环境压力下磨练他们的健康。实验室的最新进展已经 确定了改变CPS附着和丰度的特定基因和一些环境信号。 我们建议的项目领域是研究(1)控制CPS依恋的机制和 外膜释放和(2)外部营养源和细胞代谢如何调节 CPS生物合成。我们研究计划的总体愿景是开发一个模型，说明细胞外如何 信号与遗传和调控的异质性相结合，创造了动态的表面暴露的多糖 在细菌种群内增强整体适应能力，以应对环境挑战。这将是 为确定可针对其进行调节的潜在干预点奠定基础 细菌CPS的产生和对特定利基的非殖民化。

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.