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

项目摘要 缺锌是一个与早产有关的全球性问题。锌补充剂也被证明可以 预防早产，但临床研究的不同结果表明，某些尚未确定的， 人们可能会比其他人更多地受益于锌。考虑到感染作为 早产，特别是在受微量营养素缺乏影响的地区，可能是低锌水平 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，它可以侵袭宫内 羊水和感染发育中的胎儿。围产期感染GBS的风险在以下地区最高 微量营养素缺乏症很常见。为了引起宫内感染，GBS必须首先定植于阴道，在那里 低pH值可促进生物膜的形成。阴道粘膜抵抗非共生菌的定植 通过包括S100A家族蛋白(S100A8/A9和S100A12)在内的一系列抗菌分子， 通过锌离子螯合参与营养免疫。中性粒细胞也在细菌的部位分泌这些蛋白质。 感染。我们有新的令人兴奋的数据表明，缺锌会引起行为的重大变化。 对生物膜的形成有很强的影响，这种结构有助于细菌在体内的持久性 环境，我们推测这对阴道定植很重要。此外，我们还发现， GBS编码一种锌外流决定因素，CaD，它促进GBS对锌中毒的抵抗力，存活 巨噬细胞内的持久性，以及怀孕宿主的上升感染。鉴于此，我们假设 缺锌，特别是在怀孕的情况下，会增加患阴道GBS的风险 殖民和侵袭性感染。我们将通过确定锌的动态平衡对 细菌与宿主的相互作用，研究锌对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。这项工作将识别新的生物标记物 疾病风险和成本效益高的饮食或化疗策略，可以改善妊娠结局。

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.