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Calprotectin modulates Group B streptococcal colonization and disease

钙卫蛋白调节 B 族链球菌定植和疾病

基本信息

批准号：
10373060
负责人：
Kelly S Doran
金额：
$ 20.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-16 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373060
关键词：
Address Amniotic Fluid Bacterial Infections Binding Birth Cells Complement Cytoplasm Cytosol Data Disease Disease Progression Epithelial Essential Genes Female Fetal Development Gene Combinations Genes Genetic Transcription Goals Growth Homeostasis Host Defense Host Defense Mechanism Immune Immune signaling Immunologics In Vitro Individual Infant Infection Inflammation Inflammatory Inflammatory Response Invaded Ions Knockout Mice Leukocyte L1 Antigen Complex Libraries Manganese Mediating Mediator of activation protein Metals Molecular Mouse Strains Mucous Membrane Mus Neutrophil Infiltration Neutrophilic Infiltrate Newborn Infant Nutritional Immunity Outcome Permeability Pregnancy Pregnancy Complications Pregnant Women Premature Birth Premature Labor Process Production Publishing Risk Role S100A8 gene S100A9 gene Signal Transduction Site Spontaneous abortion Streptococcal Infections Streptococcus Group B Stress System Tissues Up-Regulation Uterus Vagina Virulence Woman Zinc adverse pregnancy outcome amniotic cavity chelation combat cytokine defense response dimer host colonization in vivo in vivo Model insight intrauterine infection mouse model mutant neutralizing antibody neutrophil opportunistic pathogen pathogen protein complex reproductive tract response stillbirth transmission process transposon sequencing uptake vaginal mucosa zinc-binding protein

项目摘要

PROJECT SUMMARY During bacterial infection, the host produces numerous factors that limit metals at the site of infection in a process termed nutritional immunity. The goal of this proposal is to identify mechanisms utilized by Group B Streptococcus (GBS) to evade nutritional immunity in order to persist within the vaginal mucosa and cause intrauterine infection. GBS asymptomatically colonizes the vaginal tract of 25-30% of healthy women but can ascend and preterm labor or birth, miscarriage, or stillbirth. Intrauterine infection leads to massive neutrophil influx and inflammation, where 50% of the cytoplasm of infiltrating neutrophils is calprotectin, a protein complex that upon release sequesters metal ions. During infection, GBS encounters high concentrations of calprotectin and must be able to overcome this stress, but the interaction of GBS with host calprotectin remains unknown. Our preliminary data show that calprotectin can inhibit GBS growth and studies utilizing a newly constructed saturated GBS transposon (Tn) sequencing mutant library revealed significantly underrepresented mutants in zinc transport systems following calprotectin exposure. We hypothesize that zinc transport machinery is important for GBS survival during calprotectin stress, and further that calprotectin may serve as a pro-inflammatory effector molecule, acting to compromise barrier function during GBS infection. This proposal seeks to elucidate the molecular mechanisms by which GBS overcomes calprotectin-mediated nutritional immunity in the female reproductive tract, and the role of calprotectin in ascending infection. These questions will be addressed with both in vitro and in vivo models of GBS vaginal colonization and ascending infection in the following specific aims: AIM 1: Characterize and identify the molecular determinants utilized by GBS to combat nutritional immunity during vaginal colonization; AIM 2: Determine the role of calprotectin as a modulator of reproductive tract inflammation and barrier integrity during GBS infection. These studies are the first to examine GBS metal homeostasis and the pro-inflammatory effects of calprotectin during GBS vaginal colonization, which will provide fundamental insights toward our understanding of GBS mucosal persistence and transmission to the vulnerable newborn. from the vagina into the uterus and invade the amniotic cavity, leading to inflammation, tissue damage, adverse pregnancy outcomes, including

项目摘要在细菌感染期间，宿主产生许多因素，限制感染部位的金属这一过程被称为营养免疫。本提案的目的是确定B组使用的机制链球菌（GBS）逃避营养免疫，以持续存在于阴道粘膜内，宫内感染GBS无症状地定植于25-30%的健康女性的阴道，但可以 ascend 以及早产或分娩、流产或死胎。宫内感染导致大量中性粒细胞流入和炎症，其中50%的细胞质浸润嗜中性粒细胞中的钙卫蛋白是一种蛋白质复合物，其在释放时螯合金属离子。感染期间，GBS 遇到高浓度的钙卫蛋白，必须能够克服这种压力，但相互作用 GBS伴宿主钙卫蛋白仍未知。我们的初步数据表明，钙卫蛋白可以抑制GBS 利用新构建的饱和GBS转座子（Tn）测序突变体文库的生长和研究揭示了显着代表性不足的突变体在锌转运系统后钙卫蛋白暴露。我们假设锌转运机制对于钙卫蛋白应激期间GBS存活是重要的，并进一步钙卫蛋白可能作为促炎效应分子，在GBS感染期间。该建议旨在阐明GBS克服钙卫蛋白介导的女性生殖道营养免疫，以及钙卫蛋白在上行性感染这些问题将在体外和体内模型GBS阴道解决定殖和上行感染，具体目标如下：目的1：表征和鉴定 GBS在阴道定植期间对抗营养免疫的分子决定簇; AIM 2：确定钙卫蛋白作为生殖道炎症和屏障完整性调节剂的作用， GBS感染。这些研究是第一次检查GBS金属稳态和促炎作用钙卫蛋白在GBS阴道定植，这将为我们提供基本的见解，了解格林-巴利综合征粘膜持续性和向脆弱新生儿的传播。从阴道进入子宫并侵入羊膜腔，导致炎症、组织损伤，不良妊娠结局，包括