Deciphering mechanisms of Listeria placental-fetal invasion

破译李斯特菌胎盘-胎儿侵袭机制

基本信息

批准号：
9234679
负责人：
Nancy Elizabeth Freitag
金额：
$ 23.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234679
关键词：
Amino Acids Antibiotic Therapy Bacteria Binding Birth Brain Abscess Cardiac Cardiac Myocytes Cell surface Cells Cellular Metabolic Process Cessation of life Child Clinical Data Death Rate Disease Embryonic Development Exhibits Fetal Diseases Fetal Tissues Fetus Food Food Contamination Food Processing Gentamicins Goals Growth Factor Receptors Health Heart Heparin Heparitin Sulfate Human Immunocompromised Host In Vitro Individual Infant Infection Ingestion InlB protein Invaded Lead Listeria Listeria monocytogenes Membrane Proteins Meningitis Meningoencephalitis Modification Mothers Mus Neonatal Organ Organism Pathology Pharmaceutical Preparations Placenta Placentation Pregnancy Pregnant Women Process Recording of previous events Recruitment Activity Risk Signal Pathway Spontaneous abortion Surface Teratogenic effects Testing Tissues Treatment Efficacy Unspecified or Sulfate Ion Sulfates Variant Vertical Disease Transmission Woman Work abortion base cell type fetal fetal infection foodborne foodborne outbreak heart cell high risk population individual patient insight mortality neonate novel novel therapeutic intervention older patient overexpression pathogen promoter receptor receptor binding stillbirth tissue tropism trait transmission process

项目摘要

Project Summary Listeria monocytogenes (Lm) is a facultative gram-positive intracellular bacterium that causes infection in humans via ingestion of contaminated food. Severe infection can occur in elderly and immunocompromised patients well as in pregnant women and neonates. Infection can lead to meningitis, meningoencephalitis, brain abscess, and, for pregnant women, abortion, still-birth, and disseminated fetal infection. The high mortality rate of invasive Lm disease despite antibiotic treatment highlights the need for new effective therapeutic strategies for managing Lm infections. Previous studies have shown that distinct isolates of Lm can exhibit different tissue tropisms, resulting in the acquisition of novel target organ replication niches. A clinical Lm isolate, 07PF0776, was found to have an enhanced ability to target cardiac tissue based on amino acid variations present within InlB, a bacterial surface protein associated with host cell invasion. These amino acid variations appear to increase stability and promote binding to host surface heparin sulfate moieties, which results in recruitment of InlB to the host cell surface and stimulation of Met, the receptor bound by InlB. The Met receptor is abundantly expressed by placental tissue and is required for embryonic and placental development. Preliminary data has shown at least two Lm cardiotropic strains expressing the InlB variant exhibit significantly enhanced vertical transmission. We hypothesize that modification of InlB can expand the tissue repertoire of Lm and enhance invasion through the manipulation of Met signaling pathways, leading to increased rates of fetal transmission. The specific aims of this proposal will undertake a functional assessment of Lm InlB variant strains to examine their efficacy of vertical transmission as well as determine the mechanisms by which overexpression and/or increased stability of InlB increases vertical transmission. Aim 1 will undertake a functional assessment of cardiotropic strains for efficiency of vertical transmission to define and identify strains of Lm that pose an enhanced risk for fetal disease. Aim 2 will determine the mechanisms by which overexpression of InlB increases Lm vertical transmission. These studies will thus 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) 是一种兼性革兰氏阳性细胞内细菌，可引起人类通过摄入受污染的食物而受到感染。严重感染可发生在老年人和免疫功能低下的患者以及孕妇和新生儿。感染可能导致脑膜炎、脑膜脑炎、脑脓肿，以及孕妇的流产、死产和胎儿播散性感染。尽管使用抗生素，侵袭性 Lm 病的死亡率仍然很高治疗强调需要新的有效治疗策略来控制 Lm 感染。先前的研究表明，Lm 的不同分离株可以表现出不同的组织向性，从而导致获得新的靶器官复制生态位。发现临床 Lm 分离株 07PF0776 基于体内存在的氨基酸变化，增强靶向心脏组织的能力 InlB，一种与宿主细胞侵袭相关的细菌表面蛋白。这些氨基酸变异似乎增加了稳定性并促进与宿主表面硫酸肝素部分的结合，这导致 InlB 募集到宿主细胞表面并刺激 Met（Met 结合的受体） InlB。 Met 受体在胎盘组织中大量表达，是胚胎和胚胎发育所必需的。胎盘发育。初步数据显示至少有两种 Lm 心肌菌株表达 InlB 变体表现出显着增强的垂直传输。我们假设修改 InlB 可以扩大 Lm 的组织库并通过操纵 Met 增强侵袭信号通路，导致胎儿传播率增加。本提案的具体目标将对 Lm InlB 变异菌株进行功能评估，以检查其垂直治疗的功效传播以及确定过度表达和/或增加稳定性的机制 InlB 增加垂直传输。目标 1 将进行心脏功能评估垂直传播效率的应变来定义和识别 Lm 的应变，这些应变构成了胎儿患病的风险增加。目标 2 将确定过度表达的机制 InlB 增加 Lm 垂直传输。因此，这些研究将阐明选择 Lm 如何隔离增益高效接触胎盘/胎儿组织，导致毁灭性的新生儿疾病和死亡。