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: 10358527
• 负责人: Ryan S Doster
• 金额: $ 2.87万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358527
• 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.

项目总结