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.

Public Health Relevance

Infections of the gastrointestinal tract leading to diarrhea and dysentery are a major cause of illness and death in the world. This project will investigate two enteric pathogens that are strongly implicated in a recent epidemiological study of enteric disease as important agents of lethal enteric disease, Shigella and diarrheagenic E. coli. Clinical specimens and bacteria isolated from patients will be studied to give insights into how these bacteria cause disease and death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090873-03
Application #
8292147
Study Section
Special Emphasis Panel (ZAI1-BLG-M (M2))
Program Officer
Baqar, Shahida
Project Start
2010-07-20
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,409,507
Indirect Cost
$405,971
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kania, Dane A; Hazen, Tracy H; Hossain, Anowar et al. (2016) Genome diversity of Shigella boydii. Pathog Dis 74:ftw027
Martinez de la Peña, Claudia F; De Masi, Leon; Nisa, Shahista et al. (2016) BfpI, BfpJ, and BfpK Minor Pilins Are Important for the Function and Biogenesis of Bundle-Forming Pili Expressed by Enteropathogenic Escherichia coli. J Bacteriol 198:846-56
Hazen, Tracy H; Donnenberg, Michael S; Panchalingam, Sandra et al. (2016) Genomic diversity of EPEC associated with clinical presentations of differing severity. Nat Microbiol 1:15014
Hazen, Tracy H; Leonard, Susan R; Lampel, Keith A et al. (2016) Investigating the Relatedness of Enteroinvasive Escherichia coli to Other E. coli and Shigella Isolates by Using Comparative Genomics. Infect Immun 84:2362-71
Faherty, Christina S; Wu, Tao; Morris, Carolyn R et al. (2016) The synthesis of OspD3 (ShET2) in Shigella flexneri is independent of OspC1. Gut Microbes 7:486-502
Hazen, Tracy H; Kaper, James B; Nataro, James P et al. (2015) Comparative Genomics Provides Insight into the Diversity of the Attaching and Effacing Escherichia coli Virulence Plasmids. Infect Immun 83:4103-17
Donnenberg, Michael S; Hazen, Tracy H; Farag, Tamer H et al. (2015) Bacterial Factors Associated with Lethal Outcome of Enteropathogenic Escherichia coli Infection: Genomic Case-Control Studies. PLoS Negl Trop Dis 9:e0003791
Lindsay, Brianna; Oundo, Joe; Hossain, M Anowar et al. (2015) Microbiota that affect risk for shigellosis in children in low-income countries. Emerg Infect Dis 21:242-50
Hazen, Tracy H; Daugherty, Sean C; Shetty, Amol et al. (2015) RNA-Seq analysis of isolate- and growth phase-specific differences in the global transcriptomes of enteropathogenic Escherichia coli prototype isolates. Front Microbiol 6:569
Kessler, Robert; Nisa, Shahista; Hazen, Tracy H et al. (2015) Diarrhea, bacteremia and multiorgan dysfunction due to an extraintestinal pathogenic Escherichia coli strain with enteropathogenic E. coli genes. Pathog Dis 73:ftv076

Showing the most recent 10 out of 33 publications