Deciphering mechanisms of Listeria placental-fetal invasion

破译李斯特菌胎盘-胎儿侵袭机制

• 批准号: 10436619
• 负责人: Nancy Elizabeth Freitag
• 金额: $ 39.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-14 至 2022-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436619
• 关键词: Amino Acids; Antibiotic Therapy; Bacteria; Bacterial Infections; Binding; Birth; Brain Abscess; Cardiac; Cardiac Myocytes; Cell surface; Cells; Cellular Metabolic Process; Cessation of life; Data; Disease; Embryonic Development; Exhibits; Fetal Death; Fetal Development; Fetal Tissues; Fetus; Food; Food Processing; Frequencies; Functional disorder; Genetic Crosses; Gentamicins; Goals; Growth Factor Receptors; Health; Heart; Human; Immune response; Immune signaling; Immunocompromised Host; In Vitro; Infection; Injury; InlB protein; Listeria; Listeria monocytogenes; Membrane Proteins; Meningitis; Meningoencephalitis; Modification; Molecular; Mothers; Mus; Neonatal; Organism; Pathogenicity; Pathology; Pharmaceutical Preparations; Placenta; Placentation; Play; Pregnancy; Pregnancy Outcome; Pregnant Women; Proteins; Recording of previous events; Resistance; Role; Signal Pathway; Spontaneous abortion; Surface; Teratogenic effects; Tertiary Protein Structure; Tissues; Variant; Vertical Disease Transmission; Virulence; Woman; Work; Zika Virus; base; cell type; fetal; fetal immunity; fetal infection; foodborne; foodborne outbreak; high risk population; in vivo; individual patient; infant infection; insight; microorganism; mortality; novel therapeutic intervention; older patient; pathogen; pathogenic bacteria; pregnant; receptor; receptor binding; stillbirth; tissue tropism; transmission process; uptake; viral resistance; wasting

Project Summary Listeria monocytogenes (Lm) is a gram-positive food-borne intracellular bacterial pathogen that is capable of causing serious invasive disease in humans. As a widespread environmental organism, Lm is a frequent contaminant of food processing facilities and has been responsible for some of the largest, most expensive, and most deadly food recalls in US history. Lm is one of a select number of pathogens that is transmitted during pregnancy from mother to fetus. These infections can be devastating, as often an infected woman does not even realize she has been infected with Lm until she miscarries or gives birth to a stillborn or systemically infected infant. The high mortality rate and devastating sequelae that accompany Lm invasive disease despite antibiotic treatment underlie the critical need for new therapeutic strategies to safely and effectively manage Lm invasive infections. We have recently discovered that select isolates of Lm have an enhanced ability to target the placenta and fetus based on increased expression of the bacterial surface protein InlB. Increased InlB is sufficient to transform a strain that normally exhibits a low frequency of fetal colonization to a strain that is capable off nearly 100% fetal infection. Naturally occurring amino acid variations within InlB may both increase protein stability and enhance stimulation of c-Met, the host growth factor receptor bound by InlB. Met is abundantly expressed by placental tissue and is required for embryonic and placental development. We hypothesize that Lm strains expressing select variants of InlB exhibit enhanced invasion through the manipulation of c-Met signaling pathways, leading to increased rates of fetal transmission. These strains additionally stimulate a robust immune response that leads to placental barrier dysfunction and fetal death. The specific aims of this proposal will undertake a functional assessment of Lm InlB to reveal molecular mechanisms underlying vertical transmission as well as examine the contributions of maternal and fetal immune signaling to pregnancy outcome. Aim 1 will functionally define the mechanisms underlying InlB surface localization and activity. This aim will define mechanisms that contribute to InlB stability at the bacterial cell surface and will examine functional differences between surface localization and secretion. Aim 2 will decipher the mechanisms underlying InlB enhancement of Lm vertical transmission. We will examine and compare portals of Lm entry in pregnant mice, and explore host responses to Lm infection that influence pregnancy outcome. Aim 3 will explore maternal and fetal defenses triggered by high efficiency vertically transmitted strains that contribute to pathology. These studies will clarify how select Lm isolates gain access with high efficiency to placental/fetal tissues to cause devastating forms of neonatal disease and death.

项目概要 单核细胞增生李斯特菌 (Lm) 是一种革兰氏阳性食源性细胞内细菌病原体， 能够引起人类严重的侵袭性疾病。作为一种广泛存在的环境生物， Lm 是食品加工设施中常见的污染物，是导致某些问题的原因之一。 美国历史上最大规模、最昂贵、最致命的食品召回事件。 Lm 是选定数量之一 怀孕期间从母亲传播给胎儿的病原体。这些感染可能是 毁灭性的，因为受感染的妇女常常甚至没有意识到自己已经感染了 Lm，直到 她流产或生下死产或全身感染的婴儿。高死亡率和 尽管抗生素治疗，但伴随 Lm 侵袭性疾病的毁灭性后遗症是 迫切需要新的治疗策略来安全有效地管理 Lm 侵袭性感染。 我们最近发现 Lm 的精选分离株具有增强的靶向胎盘的能力 和胎儿基于细菌表面蛋白InlB表达的增加。 InlB 增加是 足以将通常表现出低胎儿定植频率的菌株转化为菌株 几乎可以100%消除胎儿感染。 InlB 中天然存在的氨基酸变异 可能会增加蛋白质稳定性并增强对宿主生长因子受体 c-Met 的刺激 受 InlB 约束。胎盘组织大量表达蛋氨酸，是胚胎和胚胎发育所必需的。 胎盘发育。我们假设表达 InlB 特定变体的 Lm 菌株表现出 通过操纵 c-Met 信号通路增强侵袭，从而导致发生率增加 胎儿传播。这些菌株还刺激强大的免疫反应，从而导致 胎盘屏障功能障碍和胎儿死亡。该提案的具体目标将采取 Lm InlB 的功能评估揭示垂直传播的分子机制 并检查母体和胎儿免疫信号对妊娠结局的贡献。目的 图1将在功能上定义InlB表面定位和活性的潜在机制。这一目标将 定义有助于细菌细胞表面 InlB 稳定性的机制，并将检查 表面定位和分泌之间的功能差异。目标 2 将破译其机制 Lm 垂直传输的潜在 InlB 增强。我们将检查和比较 Lm 的门户 进入怀孕小鼠，并探索宿主对影响妊娠结局的 Lm 感染的反应。 目标 3 将探索高效率垂直传播引发的母体和胎儿防御 有助于病理学的菌株。这些研究将阐明选择 Lm 分离株如何获得访问权 对胎盘/胎儿组织具有高效率，可导致毁灭性的新生儿疾病和死亡。