Diarrheal diseases are a major killer of children under the age of 5 years (U5) around the worid. Despite this long-recognized association, the precise causes of severe disease remain enigmatic. In an ongoing multisite study of diarrhea in U5 children, the PI will generate a priceless archive of bacterial isolates, fecal nucleic acids and frozen stools themselves from up to 14,000 cases and matched controls. We will leverage this unparalleled set of specimens, in the context of outstanding laboratory investigations into enteric pathogenesis, to address longstanding and critically important research questions. This work will be organized in 3 specific aims.
Aim 1. Host genomic biomarkers associated with severe outcome in enteric disease. We will leverage our extensive database and specimen collection to determine the importance of single nucleotide polymorphisms (SNPs) previously associated with diarrhea, including IL-8, IL-10, lactofen'in, and osteoprotegerin genes. We will score these SNPs in host DNA from stool samples and correlate these findings with presence of severe diarrhea and death in the study database.
Aim 2. Bacterial interaction in Diarrheal Disease. Most pathogenesis research examines the behavior of a single organism in pure culture, yet the real worid comprises innumerable interactions among living organisms. Our extensive laboratory expertise in pathogenesis allows us to formulate hypothesis-driven questions about the roles of inter-bacterial interaction in the study subjects.
Aim 3. Pathogenomics of Shigella species. We will work with the University of Maryland Institute for Genome Sciences to perform the most comprehensive genomic study of Shigella strains ever performed, leveraging the availability of clinically characterized strains. Preliminary studies have revealed certain previously unsuspected genes that are more common among Shigella isolates from Kenyan patients who died of their disease. The association of these genes with severe diarrhea will be tested. This study will advance our knowledge of the most diarrhea cases in U5 subjects.

Public Health Relevance

Diarrhea is a major killer of children under the age of 5 years. We found that certain types of bacteria are particulariy deadly. We will identify all the genes in strains of bacteria from children who died of diarrhea and compare these genes to those of similar strains from children with diarrhea who did not die. Genes of the children will also be studied to determine any correlation with lethal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090873-05
Application #
8683082
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
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

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