E. coli niche expansion and adaptation in the dysbiotic intestine

肠道菌群失调中的大肠杆菌生态位扩张和适应

• 批准号: 9164506
• 负责人: Mark D Goulian
• 金额: $ 24.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9164506
• 关键词: Affect; Amino Acids; Antibiotic Therapy; Bacteria; Biological Models; Chronic; Enabling Factors; Enterobacteriaceae; Environment; Escherichia coli; Gastrointestinal tract structure; Genes; Genetic; Genetic Determinism; Genome; Gnotobiotic; Growth; Immune response; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Lead; Lipopolysaccharides; Maintenance; Mediator of activation protein; Modeling; Modification; Mus; Mutation; Nature; O Antigens; Play; Polysaccharides; Population; Population Sizes; Procedures; Research; Role; Signal Transduction; Stress; System; Testing; Virulence; Work; antimicrobial peptide; combat; in vivo; membrane-associated placental tissue protein 1; microbiota; mouse model; mutant; novel therapeutic intervention; novel therapeutics; pathogenic Escherichia coli; pressure; response

The research in this proposal will explore the genetic components that enable commensal E. coli to expand their niche in the context of intestinal dysbiosis associated with inflammation. The work will take advantage of a new E. coli commensal colonization model in mice that allows the growth of competing flora, and will focus on genes that are not required for colonization of healthy mice. The first aim will test the role of the PhoQ/PhoP signal transduction system, as well as additional two-component systems, in enabling adaptation to the expanded niche that leads to blooms during inflammation. The second aim will focus on the role of genes associated with an O-polysaccharide decoration that is detrimental to colonization under standard conditions. This aim will test the hypothesis that this decoration provides protection in the environment of the inflamed intestine. An understanding of the mechanisms that enable adaptation to dysbiotic environments and the role of blooms in imposing selective pressures on the E. coli genome will lead to a better understanding of the dynamic environment of the gastrointestinal tract and to potential strategies for controlling dysbiosis. In addition, many genes required for survival in the context of inflammation may also be important for infection by pathogenic E. coli isolates, either in intestinal or extra-intestinal environments. Thus the selective pressure to bloom during chronic or intermittent inflammation may be critical for the maintenance of genes that contribute to the virulence of pathogenic E. coli. This may lead to new therapies to combat and limit the spread of pathogenic E. coli and related bacteria.

这项研究计划将探索使Escherosal E.大肠杆菌进行扩增 它们在与炎症相关的肠道生态失调的背景下的生态位。这项工作将利用一个 新E.大肠杆菌在小鼠体内的定植模型，该模型允许竞争性植物群的生长，并将重点关注 这些基因不是健康小鼠定植所必需的。第一个目标将测试PhoQ/PhoP的作用 信号转导系统，以及额外的双组分系统，使适应 扩大的壁龛，导致在炎症期间开花。第二个目标将集中在基因的作用 与在标准条件下对定殖有害的O-多糖装饰相关。 这一目标将测试的假设，这种装饰提供保护的环境中发炎 肠子了解能够适应生态失调环境的机制以及 对E.大肠杆菌基因组将导致更好地了解 胃肠道的动态环境和控制生态失调的潜在策略。在 此外，在炎症环境中生存所需的许多基因也可能对感染很重要， 致病性大肠大肠杆菌分离株，无论是在肠道或肠道外的环境。因此，选择性压力， 在慢性或间歇性炎症期间的开花可能对维持基因至关重要， 致病性E.杆菌这可能会导致新的疗法来对抗和限制 致病性大肠大肠杆菌和相关细菌。