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

• 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
• 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

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.

项目概要 缺锌是与早产相关的全球性问题。补充锌也被证明可以 预防早产，但临床研究的异质性结果表明，某些尚未明确的 人们可能比其他人更多地从锌中受益。鉴于感染作为原因的重要性 早产，特别是在受微量营养素缺乏影响的地区，可能是由于锌水平低 增加围产期感染的风险。然而，人们对这种可能的关系知之甚少。 B组 无乳链球菌 (GBS) 是妊娠期间宫内感染的主要原因，它可以侵入宫内。 羊水并感染发育中的胎儿。在以下地区，围产期 GBS 感染的风险最高 微量营养素缺乏很常见。要引起宫内感染，GBS 必须首先定植于阴道，其中 低pH值会刺激生物膜的形成。阴道粘膜抵抗非共生细菌的定植 通过包括 S100A 家族蛋白（S100A8/A9 和 S100A12）在内的一系列抗菌分子， 通过锌螯合参与营养免疫。中性粒细胞也在细菌的位点分泌这些蛋白质 感染。我们有令人兴奋的新数据表明缺锌会引起行为的重大变化 GBS，对生物膜的形成有很强的影响，生物膜的结构有助于细菌在环境中的持久存在 我们推测这对于阴道定植很重要。此外，我们还发现 GBS 编码锌流出决定簇 CadD，可促进 GBS 对锌中毒的抵抗力、存活率 巨噬细胞内的持续存在，以及怀孕宿主中的上行感染。鉴于此，我们假设 缺锌，特别是在怀孕期间，会导致阴道 GBS 风险增加 定植和侵袭性感染。我们将通过确定锌稳态的贡献来测试这一点 细菌-宿主相互作用，研究锌对人类妊娠期免疫反应的影响 侵袭性 GBS 感染小鼠模型中的膜和疾病进展，并评估 锌稳态对孕妇 GBS 定植的影响。这项工作将确定新的生物标志物，以增加 疾病风险和可以改善妊娠结局的具有成本效益的饮食或化疗策略。