Severe Enteric Disease: Pathogenesis and Response

描述（由申请人提供）：传染性肠道疾病是全球主要的健康问题。本申请旨在建立马里兰大学肠道研究调查网络（ERIN）合作研究中心（CRC），以研究肠道疾病的重要临床、发病机制和宿主反应问题。该CRC将重点关注的特定肠道病原体是志贺氏菌和致泻性大肠杆菌（DEC），它们被认为是全球肠道多中心研究（GEMS）中最常从致死性腹泻病例中分离出来的细菌病原体。全球监测方案正在非洲和南亚的7个地点进行，这是有史以来对5岁以下儿童腹泻病进行的最大规模的研究。临床标本和从GEMS分离的细菌以及本研究产生的假设将使用各种方法进行进一步检查，包括细菌发病机制分析，肠道生理学研究，粪便适应性免疫和免疫标记，细菌基因组学，微生物组学和人类SNP分析。提出了三个多组件、高度集成的项目。项目1将重点研究DEC和志贺氏菌感染的发病机制。将确定从致死性腹泻病例、非致死性感染和对照中分离的肠致病性大肠杆菌（EPEC）菌株的基因组序列。基因组分析中涉及的潜在EPEC毒力因子将通过各种分析和模型进一步表征，以研究发病机制。最初在志贺氏菌中发现但也存在于DEC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，包括野生型和突变型志贺氏菌和DEC菌株感染肠道组织的生理学研究，以及GEMS患者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GEMS的临床标本来研究临床方面，以确定患者先前与腹泻病易感性相关的基因的snp，使用微生物组和实验室联合感染研究进行细菌相互作用，并研究从致死性和非致死性疾病中分离的志贺氏菌菌株的全基因组学。

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.