Defining the impact of zinc on Streptococcus agalactiae biofilm and colonization

确定锌对无乳链球菌生物膜和定植的影响

• 批准号: 10721139
• 负责人: Ryan S Doster
• 金额: $ 15.68万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721139
• 关键词: Academic Medical Centers; Adult; Area; Bacterial Infections; Bacterial Physiology; Cells; Clinical; Communicable Diseases; Complement; Core Facility; Data; Development; Epithelial; Epithelial Cells; Event; Female; Fetal Membranes; Future; Genetic; Genetic Transcription; Genomics; Glucose; Goals; Human; Immune response; Impairment; In Vitro; Infection; Inflammatory Response; Innate Immune Response; Light; Link; Medicine; Mentors; Mentorship; Microbial Biofilms; Microscopy; Modeling; Morbidity - disease rate; Mus; Mutagenesis; Newborn Infant; Nutrient; Pathogenesis; Pathway interactions; Pediatrics; Perinatal; Perinatal Infection; Physicians; Pregnancy; Pregnant Women; Premature Birth; Premature Labor; Production; Program Development; Regulator Genes; Regulatory Pathway; Research; Research Personnel; Resolution; Risk; Risk Factors; Role; Scholarship; Scientist; Stimulus; Streptococcal Infections; Streptococcus Group B; Supplementation; Techniques; Technology; Testing; Tissue membrane; Tissues; Training; United States; Vagina; Woman; Work; Zinc; Zinc deficiency; Zinc supplementation; career; career development; dietary; early onset; host colonization; human model; in vitro Model; in vivo; infection risk; innovation; instructor; instrument; intraamniotic infection; intrauterine infection; microbial host; mortality; mouse model; multidisciplinary; mutant; neonatal infection; neonatal sepsis; novel strategies; organ on a chip; pathogen; premature; prevent; reproductive tract; response; stillbirth; transcriptome; transcriptomics; zinc-binding protein

Project Summary During pregnancy, zinc deficiency is associated with an increased risk of infection. Streptococcus agalactiae, also known as Group B Streptococcus (GBS), colonizes 20-30% of pregnant women. GBS vaginal colonization increases the risk for stillbirth, preterm labor, and neonatal sepsis. One strategy that GBS may use to stably colonize the reproductive tract is to produce biofilm, and we have found that GBS biofilm production is suppressed in the presence of zinc. This proposal tests the hypothesis that GBS biofilm production is negatively regulated by zinc, and this biofilm contributes to stable colonization of host tissues by limiting innate immune responses against GBS. To test this hypothesis, Aim 1 will use mutagenesis and transcriptomic approaches to identify genetic pathways regulating GBS biofilm. Aim 2 will define the impact of zinc-regulated biofilm at the host-microbial interface by evaluating GBS mutants lacking cadD, a zinc efflux transporter, which results in impaired biofilm production. We will examine these interactions using in vitro models of human vaginal epithelial cells, explanted human fetal membranes, and an Instrumented Fetal Membrane Organ on a Chip (IFMOC) model under conditions that modify zinc availability. Aim 3 will use a mouse vaginal colonization model to define how the zinc transporter, cadD, impacts vaginal colonization in settings of zinc deficiency or supplementation. Completion of these Aims will shed new light on how zinc impacts GBS-host interactions that culminate in colonization (and infection) of the reproductive tract. Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center. His past work investigated gestational tissue innate immune responses to infection. This project will expand his research focus to mechanisms of GBS colonization. This project complements Dr. Doster’s clinical training in pediatrics and adult infectious diseases medicine. Under the mentorship of Dr. David Aronoff, Dr. Jennifer Gaddy, and a multidisciplinary Scholarship Oversight Committee, Dr. Doster will master techniques including bacterial mutagenesis, transcriptomics, and modeling infection within the reproductive tract to determine how zinc alters bacterial physiology and pathogenesis. Vanderbilt offers cutting-edge technology and expertise in these areas through Vanderbilt Technologies for Advanced Genomics and other shared research core facilities. These studies and a strong career development program will prepare Dr. Doster for transition to an independent researcher investigating the pathogenesis of bacterial infections during pregnancy.

项目摘要 在怀孕期间，锌缺乏症与感染的风险增加有关。 也称为B组链球菌（GBS），将20-30％的孕妇定居 增加死产，早产劳动和新生儿败血症的风险。 殖民地的生殖道是产生生物膜 在存在锌的情况下进行的suppss。 由锌定期定制的阴性，这种生物膜通过限制先天而导致宿主组织的稳定定植 针对GB的免疫反应。 确定调节GBS生物膜的遗传途径的方法。 通过评估缺少CADD的GBS突变体（锌外排运输蛋白）的GBS突变体，该突变体在宿主微生物界面处的生物膜（生物膜） 结果损害生物膜的产生。 阴道上皮细胞，外植的人类胎儿膜和仪器上的胎儿器官 在修改锌可用性的条件下，芯片（IFMOC）模型将使用小鼠阴道定植 定义锌转运蛋白CADD的模型如何影响锌的环境中的阴道定植 这些目标的补充将为锌的影响如何影响GBS-HOST的相互作用 在繁殖道的定植（和感染）中达到最终。 Ryan Doster博士是范德比尔特大学医学中心感染学系的讲师。 他过去的工作调查了妊娠组织对感染的先天免疫反应。 研究重点是GBS殖民机制。 小儿科和成人传染病医学。 Gaddy和多学科奖学金监督委员会，Doster博士将掌握包括 细菌性毒素，转录组学和繁殖中的建模感染，以确定如何 锌改变细菌的生理和发病机理。 这些领域通过范德比尔特技术技术和其他共享的研究核心核心核心核心核心核心核心 这些研究和强大的职业发展计划将使Doster博士 独立的研究人员研究了预言期间双期感染的发病机理。