Deciphering mechanisms of Listeria placental-fetal invasion

破译李斯特菌胎盘-胎儿侵袭机制

• 批准号: 10363099
• 负责人: Nancy Elizabeth Freitag
• 金额: $ 46.14万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363099
• 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; Genetic Variation; 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; gene product; 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.

项目摘要 单核细胞增生李斯特菌（LM）是一种革兰氏阳性食品 - 细胞内细菌病原体 能够在人类中引起严重的侵入性疾病。作为广泛的环境生物， LM是食品加工设施的常见污染物，已负责某些 美国历史上最大，最昂贵，最致命的食物回忆。 LM是精选的数量之一 怀孕期间从母亲到胎儿传播的病原体。这些感染可能是 毁灭性的，因为经常被感染的女人甚至没有意识到她已经被LM感染了，直到 她流产或生下死产或系统感染的婴儿。高死亡率和 尽管抗生素治疗是由 对新的治疗策略的批判性需求，以安全有效地管理LM侵入性感染。 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 基于细菌表面蛋白INLB表达的增加和胎儿。 INLB的增加IS 足以转化通常表现出低频率胎儿定植为菌株的菌株 这能够消除近100％的胎儿感染。 INLB内的天然存在的氨基酸变化 既可以提高蛋白质稳定性并增强C-MET的刺激，宿主生长因子受体受体 由INLB约束。 Met通过胎盘组织大量表达，并且是胚胎和 胎盘发展。我们假设表达INLB的某些变体的LM菌株展示了 通过操纵C-MET信号通路增强了入侵，导致速率提高 胎儿传播。这些菌株还刺激了可靠的免疫反应，导致 胎盘屏障功能障碍和胎儿死亡。该提案的具体目的将实施 LM INLB的功能评估，以揭示垂直传播的分子机制 以及检查母体和胎儿免疫信号传导对妊娠结局的贡献。目的 1将在功能上定义INLB表面定位和活性的基础机制。这个目标 定义有助于细菌细胞表面INB稳定性的机制，并将检查 表面定位和分泌之间的功能差异。 AIM 2将破译机制 LM垂直传输的基础INLB增强。我们将检查和比较LM的门户 进入怀孕小鼠，并探索影响妊娠结局的LM感染的宿主反应。 AIM 3将探索由高效率垂直传播触发的母亲和胎儿防御 导致病理学的菌株。这些研究将阐明选择LM分离株如何通过 对胎盘/胎儿组织的高效率引起了新生儿疾病和死亡的毁灭性形式。