Deciphering how bacterial pheromone signaling enhances Listeria virulence

破译细菌信息素信号如何增强李斯特菌毒力

基本信息

批准号：
8965502
负责人：
Nancy Elizabeth Freitag
金额：
$ 23.98万
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：
2014
资助国家：
美国
起止时间：
2014-11-06 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8965502
关键词：
Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Bacterial Meningitis Biochemical Brain Abscess Cardiac Cells Cessation of life Competence Critical Pathways Cytolysis Cytosol DNA Development Disease Disease Outbreaks Disease Reservoirs Elderly Enterococcus faecalis Environment Exhibits Food Contamination Gastroenteritis Gene Expression Genetic Gentamicins Goals Gram-Positive Bacteria Health Immunocompromised Host Individual Infection Lead Life Lipoproteins Listeria Listeria monocytogenes Location Mammalian Cell Mediating Membrane Meningitis Meningoencephalitis Microbe Microbial Biofilms Molecular Neurologic North America Organism Pathogenesis Pathway interactions Pattern Peptide Signal Sequences Peptides Perforation Pharmaceutical Preparations Pheromone Physiological Processes Placenta Population Pregnant Women Process Production Recording of previous events Regulon Relapse Reporting Research Risk Septicemia Severities Severity of illness Signal Pathway Signal Transduction Soil System Treatment Protocols Vacuole Virulence Virulence Factors Work abortion bacteriocin base cell transformation design foodborne foodborne outbreak gene product human disease in vivo interest mortality neonate novel novel strategies older patient pathogen stillbirth tool uptake

项目摘要

DESCRIPTION (provided by applicant): Listeria monocytogenes (Lm) is a food-borne facultative intracellular bacterial pathogen that has been responsible for some of the deadliest contaminated food outbreaks in U.S. history. While disease in healthy individuals is usually limited to gastroenteritis, serious invasive disease occurs in susceptible populations that include immunocompromised individuals, pregnant women, neonates, and the elderly. Lm infections are commonly associated with meningitis, meningoencephalitis, brain abscesses, cardiac infections, septicemia, or stillbirth and abortion in pregnant women. Invasive disease resulting from Lm infection has a mortality rate that ranges from approximately 20% to up to 66% or higher despite antibiotic treatment, and surviving individuals often suffer from debilitating neurological sequelae. New effective strategies for successful treatment of Lm invasive infections are urgently needed to limit the severity of disease and the serious post-infection sequelae. In addition, a broader understanding of the molecular adaptations that enable Lm to transition from soil saprophyte to pathogen may facilitate better assessment of environmental reservoirs of disease. The focus of this proposal is on deciphering how a novel bacterial peptide pheromone-based signaling system enables a soil bacterium to transition into life within the mammalian cytosol. Central to the Lm soil-to-cytosol transition is the ability of the bacterium to sense its location within the vacuoles of infected host cells and express gene products that promote vacuole lysis and bacterial escape into the cytosol where replication occurs. We have identified a bacterial peptide pheromone that enhances Lm escape from host vacuoles and which is required for bacterial virulence in animals. The working hypothesis of this R21 proposal is that the pPplA peptide pheromone enables Lm to sense the spatial confines of the vacuole and induce the expression of gene products necessary for vacuole escape and cytosolic replication. This proposal will use a combination of genetic, biochemical, and in vivo approaches to functionally decipher the contributions of the pPplA peptide pheromone to bacterial virulence. Aim 1 will define the expression patterns and components of the pPplA signaling pathway, and Aim 2 will determine the mechanism by which pPplA enhances bacterial escape from host vacuoles. The ultimate goal of this proposal will be to elucidate the molecular pathways that promote Lm survival within host cells and the transformation of a soil dweller into a cell invader.

描述（由申请人提供）：单核细胞增生李斯特菌 (Lm) 是一种食源性兼性细胞内细菌病原体，它是美国历史上一些最致命的污染食品爆发的原因，而健康个体的疾病通常仅限于胃肠炎、严重的侵袭性食品。疾病发生在易感人群中，包括免疫功能低下的个体、孕妇、新生儿和老年人通常会导致脑膜炎、脑膜脑炎、脑脓肿、心脏感染、败血症或孕妇的死产和流产。Lm 感染导致的死亡率不等。尽管进行了抗生素治疗，感染率仍从约 20% 上升至 66% 或更高，并且存活下来的个体经常遭受使人衰弱的神经系统后遗症，成功治疗 Lm 侵袭性感染。迫切需要限制疾病的严重程度和严重的感染后后遗症。此外，更广泛地了解使 Lm 从土壤腐生菌转变为病原体的分子适应性可能有助于更好地评估疾病的环境储存库。破译基于细菌肽信息素的新型信号系统如何使土壤细菌在哺乳动物细胞质中转变为生命，Lm 土壤到细胞质转变的核心是细菌的能力。细菌感知其在受感染宿主细胞液泡中的位置，并表达促进液泡裂解和细菌逃逸到发生复制的胞质溶胶中的基因产物。该 R21 提案的工作假设是 pPplA 肽信息素使 Lm 能够感知真空的空间范围和诱导液泡逃逸和胞质复制所需的基因产物的表达该提案将结合遗传、生化和体内方法来功能性地破译pPplA肽信息素对细菌毒力的贡献，目标1将定义表达模式。目标 2 将确定 pPplA 增强细菌逃离宿主液泡的机制。阐明促进 Lm 在宿主细胞内存活以及将土壤居民转化为细胞入侵者的分子途径。