Severe Enteric Disease: Pathogenesis and Response

严重肠道疾病：发病机制和反应

• 批准号: 8113434
• 负责人: JAMES B KAPER
• 金额: $ 145.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113434
• 关键词: Severe; Enteric; Disease; Pathogenesis; Response

DESCRIPTION (provided by applicant): Infectious enteric diseases are major health problem throughout the world. This application seeks to establish the University of Maryland Enterics Research Investigational Network (ERIN) Cooperative Research Center (CRC) to investigate important clinical, pathogenesis, and host response Issues of enteric disease. The particular enteric pathogens that will be the focus of this CRC are Shigella spp. and diarrheagenic E. coli (DEC), which were implicated as the bacterial pathogens most frequently isolated from fatal cases of diarrheal disease in the Global Enteric Multicenter Study (GEMS). The GEMS is being conducted at 7 sites in Africa and South Asia and is the largest study ever conducted of diarrheal disease in children under the age of 5. Clinical specimens and bacterial isolates from GEMS as well as hypotheses arising from this study will be further examined using a variety of approaches including bacterial pathogenesis assays, intestinal physiology studies, fecal adaptive immunity and immunological markers, bacterial genomics, microbiomes, and human SNP analysis. Three multi-component and highly integrated projects are proposed. Project 1 will focus on the pathogenesis of DEC and Shigella infections. Genome sequences of enteropathogenic E. coli (EPEC) strains isolated from lethal cases of diarrhea, from non-lethal infections and from controls will be determined. Potential EPEC virulence factors implicated in the genomic analysis will be further characterized using a variety of assays and models to study pathogenesis. An enterotoxin originally discovered in Shigella but also present in DEC will be further characterized. In Project 2, different aspects of host response will be studied, including physiology studies of intestinal tissue infected with wild type and mutant Shigella and DEC strains, as well as the characterization of fecal immunoglobulin and cytokine levels in stool specimens from GEMS patients. Project 3 will investigate clinical aspects using clinical specimens from GEMS to determine patient SNPs in genes previously associated with susceptibility to diarrheal disease, bacterial interactions using microbiome and laboratory co-infection studies, and studies on the pangenomics of Shigella strains isolated from lethal and non-lethal disease.

描述（由申请人提供）：感染性肠道疾病是全球主要的健康问题。该申请旨在建立马里兰州大学进入研究研究网络（ERIN）合作研究中心（CRC），以调查肠道疾病的重要临床，发病机理和宿主反应问题。将是该CRC的重点的特定肠道病原体是志贺氏菌属。在全球肠道多中心研究（GEMS）中，腹泻性大肠杆菌（DEC）被认为是与腹泻病致命病例最常分离的细菌病原体。 The GEMS is being conducted at 7 sites in Africa and South Asia and is the largest study ever conducted of diarrheal disease in children under the age of 5. Clinical specimens and bacterial isolates from GEMS as well as hypotheses arising from this study will be further examined using a variety of approaches including bacterial pathogenesis assays, intestinal physiology studies, fecal adaptive immunity and immunological markers, bacterial基因组学，微生物组和人类SNP分析。提出了三个多组分和高度集成的项目。项目1将集中于DEC和志贺氏菌感染的发病机理。将确定从致命的腹泻病例，非致命感染和对照组中分离出的肠病大肠杆菌（EPEC）菌株的基因组序列。与研究发病机理的各种测定和模型相关的潜在EPEC毒力因子将进一步表征。最初在志贺氏菌中发现但也存在于DEC中的肠毒素将进一步表征。在项目2中，将研究宿主反应的不同方面，包括对野生型和突变志贺氏菌和DEC菌株感染的肠道组织的生理研究，以及来自GEMS患者的粪便标本中粪便免疫球蛋白和细胞因子水平的表征。项目3将使用来自GEM的临床标本来研究临床方面，以确定先前与腹泻疾病易感性相关的基因中的患者SNP，使用微生物组和实验室共感染研究的细菌相互作用，以及对与致死和非致命疾病分离的志贺氏菌菌株的甲壳虫学的研究。