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.

项目总结