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

• 批准号: 8806236
• 负责人: Nancy Elizabeth Freitag
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-06 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806236
• 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; 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; Proteins; 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; human disease; in vivo; interest; mortality; neonate; novel; novel strategies; older patient; pathogen; public health relevance; stillbirth; tool; uptake

 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（由适用提供）：单核细胞增生李斯特氏菌（LM）是一种饮食传播的辅导性细胞内细菌病原体，负责美国历史上一些最致命的食物暴发。虽然健康个体的疾病通常仅限于胃炎 免疫功能低下的个体，孕妇，新生儿和年龄较大。 LM感染通常与脑膜炎，脑膜脑炎，脑脓肿，心脏感染，败血病或静止生日以及孕妇的流产有关。 LM感染引起的侵入性疾病的死亡率率范围从约20％到高达66％或更高，尽管抗生素治疗以及生存个体通常患有虚弱的神经系统后遗症。迫切需要采取新的有效治疗LM侵入性感染的策略，以限制疾病的严重程度和严重的感染后后遗症。此外，对能够从土壤腐生型过渡到病原体过渡的分子适应性的更广泛理解可能有助于更好地评估疾病环境储层。该提案的重点是破译新型细菌基于信息素的信号传导系统如何使土壤细菌过渡到哺乳动物细胞质内的生命。 LM土壤到胞质溶液过渡的中心是细菌感知其在感染宿主细胞真空中的位置的能力，并表达促进真空裂解的基因产物，并促进真空裂解和细菌逃脱到发生复制的细胞质中。我们已经确定了一种细菌肽信息素，可增强LM从宿主尘埃逃生，这是动物中细菌病毒所必需的。该R21提案的工作假设是，PPPLA肽信息素使LM能够感知吸尘器的空间范围，并诱导真空逃脱和胞质复制所必需的基因产物的表达。该建议将结合遗传，生化和体内方法的结合，在功能上破译PPPLA肽素对细菌病毒的贡献。 AIM 1将定义PPPLA信号通路的表达模式和成分，AIM 2将确定PPPLA增强细菌从宿主真空逃脱的机制。该提案的最终目标是阐明促进宿主细胞内LM存活的分子途径以及将土壤居民转化为细胞入侵者。