Pathogenesis

发病

• 批准号: 8683080
• 负责人: MICHAEL S DONNENBERG
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683080
• 关键词: Bacteria; Bacterial Genes; Cells; Cessation of life; Child; Clinical; Collection; Data; Development; Diagnosis; Diarrhea; Disease; Disease Outcome; Enteral; Enterotoxins; Environmental Risk Factor; Escherichia coli EHEC; Escherichia coli Infections; Genes; Genetic; Genome; Genomic Islands; Genomics; Goals; Human; Immune response; Infant; Infection; Infection Control; Infection prevention; Integration Host Factors; Laboratories; Lead; Link; Microbe; Multicenter Studies; Outcome; Pathogenesis; Patients; Proteins; Resources; Role; Sequence Analysis; Severity of illness; Shigella; Shigella Infections; Symptoms; System; Testing; Toxin; Virulence; Virulence Factors; base; enteric pathogen; enteropathogenic Escherichia coli; gastrointestinal infection; genome sequencing; in vitro Model; killings; novel; pathogen; prevent; research study; response

Gastrointestinal infections claim the lives of 2-3 million children annually. Interim data from a Global Enteric Multicenter Study indicate that a disporportionate number of deaths among children is associated with infections due to enteropathogenic E. coli (EPEC) and Shigella spp. In this project we will investigate the contribution to pathogenesis of specific factors produced by EPEC and Shigella that are associated with severe disease and we will discover new such factors in EPEC. We will determine the genome sequence of 20 EPEC strains recently isolated from children who succumbed to diarrhea, 20 strains from children with non-lethal sypmptomatic infection and 20 strains from asymptomatic control children. We will specifically seek new genetic loci that are associated with symptomatic infection and with lethal outcome. We will determine the host cell targets and mechanisms of action of two proteins, NIeB and NIeE, that are secreted by EPEC and injected into host cells and that have been associated in previous studies with increased virulence in humans. We will also determine the contributions to pathgenesis of novel EPEC genetic loci associated with virulence identified by the above genomic sequencing. And we will determine the target and mechanism of action of a protein known as ShET2 that is produced and secreted by both EPEC and Shigella, associated with increased virulence in human EPEC infection, and has been proposed but not proven to be injected into host cells. Together, these experiments will yield an unprecidented amount of data on the genetic basis of EPEC pathogenesis, uncover mechanisms of action of virulence factors from EPEC and Shigella, and in particular identify novel loci associated with deadly infections. These data will serve as an extremely valuable resource for new initiatives to prevent and treat severe enteric infections.

胃肠道感染每年夺去 2-300 万儿童的生命。全球肠道多中心研究的中期数据表明，儿童死亡人数与肠病性大肠杆菌 (EPEC) 和志贺氏菌感染有关。在这个项目中，我们将研究 EPEC 和志贺氏菌产生的与严重疾病相关的特定因子对发病机制的贡献，并且我们将在 EPEC 中发现新的此类因子。我们将确定最近从腹泻儿童中分离出的 20 株 EPEC 菌株、从非致命性症状感染儿童中分离出的 20 株 EPEC 菌株以及从无症状对照儿童中分离出的 20 株菌株的基因组序列。我们将专门寻找与症状感染和致命结果相关的新基因位点。我们将确定两种蛋白质 NIeB 和 NIeE 的宿主细胞靶标和作用机制，这两种蛋白质由 EPEC 分泌并注射到宿主细胞中，并且在之前的研究中已被证明与人类毒力增加有关。我们还将确定与上述基因组测序确定的毒力相关的新 EPEC 基因位点对发病机制的贡献。我们将确定一种名为 ShET2 的蛋白质的作用靶点和作用机制，该蛋白质由 EPEC 和志贺氏菌产生和分泌，与人类 EPEC 感染的毒力增加有关，并且已被提议但尚未证明可以注射到宿主细胞中。总之，这些实验将产生关于 EPEC 发病机制的遗传基础的大量数据，揭示 EPEC 和志贺氏菌毒力因子的作用机制，特别是确定与致命感染相关的新位点。这些数据将成为预防和治疗严重肠道感染的新举措的极其宝贵的资源。