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Determining the contribution of zinc deficiency to perinatal Group B Streptococcus infections

确定锌缺乏对围产期 B 族链球菌感染的影响

基本信息

批准号：
9381886
负责人：
David M Aronoff
金额：
$ 54.44万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381886
关键词：
Address Affect Amniotic Fluid Anti-Bacterial Agents Area Bacteria Bacterial Infections Behavior Child Clinical Clinical Research Cost of Illness Data Diet Dietary Zinc Disease Disease Outcome Disease Progression Environment Event Fetus Genetic Polymorphism Gravid Gravidity Homeostasis Host Defense Human Immune response Immune system Immunity Infection Intoxication Invaded Knowledge Lead Maternal and Child Health Membrane Microbial Biofilms Mothers Mucous Membrane Mus Nutritional Outcome Pathogenesis Perinatal Perinatal Infection Population Pregnancy Pregnancy Outcome Pregnant Women Premature Birth Premature Labor Prevention Prevention approach Protein Family Proteins Resistance Risk Role S100A12 gene S100A8 gene Serum Site Streptococcal Infections Streptococcus Group B Structure Surface Testing Time Tissues Translational Research Uterus Vagina Virulence Work Zinc Zinc deficiency Zinc supplementation antimicrobial chelation cost effective cytokine disorder risk early onset fetal infection genome sequencing improved in vivo interest intraamniotic infection low and middle-income countries macrophage microbiome micronutrient deficiency mouse model neonatal sepsis neutrophil novel novel marker novel strategies offspring pathogen pregnant premature prevent protein expression response vaginal microbiome whole genome

项目摘要

Project Summary Zinc deficiency is a global problem associated with preterm birth. Zinc supplementation has also been shown to prevent preterm birth, but heterogeneous results of clinical studies suggest that certain, as yet undefined, populations are likely to benefit from zinc more than others. Given the importance of infections as causes of preterm birth, especially in regions affected by micronutrient deficiency, it is possible that low zinc levels contribute to the risk for perinatal infections. However, little is known about this possible relationship. Group B Streptococcus agalactiae (GBS) is a major cause of intrauterine infections during pregnancy, where it can invade amniotic fluid and infect the developing fetus. The risk for perinatal GBS infections is highest in regions where micronutrient deficiency is common. To cause intrauterine infection, GBS must first colonize the vagina, where the low pH stimulates biofilm formation. The vaginal mucosa resists colonization by non-commensal bacteria through a repertoire of antimicrobial molecules including S100A-family proteins (S100A8/A9 and S100A12) that participate in nutritional immunity via zinc chelation. Neutrophils also secrete these proteins at sites of bacterial infection. We have new and exciting data to suggest that zinc deficiency provokes major changes in the behavior of GBS, with strong effects on the formation of biofilms, structures that aid in bacterial persistence in the environment, which we speculate are important for vaginal colonization. Furthermore, we have also discovered that GBS encoded a zinc efflux determinant, CadD, which promotes GBS resistance to zinc intoxication, survival and persistence within macrophages, and ascending infection in a pregnant host. Given this, we hypothesize that zinc deficiency, specifically in the context of pregnancy, leads to an increased risk for vaginal GBS colonization and invasive infection. We will test this by determining the contribution of zinc homeostasis to bacterial-host interactions, investigating the influence of zinc on immunological responses in human gestational membranes and disease progression in a mouse model of invasive GBS infection, and evaluate the impact of zinc homeostasis on GBS colonization in pregnant women. This work will identify novel biomarkers for increased disease risk and cost-effective dietary or chemotherapeutic strategies that could improve pregnancy outcomes.

项目总结