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

项目概要在细菌感染期间，宿主会产生许多因素来限制感染部位的金属过程称为营养免疫。该提案的目标是确定 B 组使用的机制链球菌（GBS）逃避营养免疫，在阴道粘膜内存在并导致宫内感染。 GBS 无症状地定植于 25-30% 健康女性的阴道，但也可上升以及早产或分娩、流产或死产。宫内感染导致大量中性粒细胞流入和炎症，其中 50% 的细胞质浸润中性粒细胞是钙卫蛋白，一种蛋白质复合物，释放后可隔离金属离子。感染期间，GBS 遇到高浓度的钙卫蛋白并且必须能够克服这种压力，但是 GBS 与宿主钙卫蛋白的关系仍然未知。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) 测序突变体文库进行生长和研究揭示了钙卫蛋白暴露后锌转运系统中代表性明显不足的突变体。我们假设锌转运机制对于钙卫蛋白应激期间 GBS 的存活很重要，并且进一步钙卫蛋白可能作为促炎效应分子，损害屏障功能 GBS感染期间。该提案旨在阐明 GBS 克服的分子机制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感染。这些问题将通过 GBS 阴道的体外和体内模型得到解决定植和上行感染的具体目标如下：目标 1：表征和识别 GBS 在阴道定植期间利用分子决定因素对抗营养免疫；目标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。这些研究是第一个检查 GBS 金属稳态和促炎作用的研究 GBS 阴道定植期间钙卫蛋白的变化，这将为我们提供基本的见解了解 GBS 粘膜的持续存在以及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

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The impact of nutritional immunity on Group B streptococcal pathogenesis during wound infection.

伤口感染期间营养免疫对 B 族链球菌发病机制的影响。

DOI：
发表时间：
2023-08-31
期刊：
影响因子：
6.4
作者：
Akbari, Madeline S;Keogh, Rebecca A;Radin, Jana N;Sanchez;Johnson, Michael D L;Horswill, Alexander R;Kehl;Burcham, Lindsey R;Doran, Kelly S
通讯作者：
Doran, Kelly S