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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BLG-M)
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University of Maryland Baltimore
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Ndungo, Esther; Randall, Arlo; Hazen, Tracy H et al. (2018) A Novel Shigella Proteome Microarray Discriminates Targets of Human Antibody Reactivity following Oral Vaccination and Experimental Challenge. mSphere 3:
Sahl, Jason W; Sistrunk, Jeticia R; Baby, Nabilah Ibnat et al. (2017) Insights into enterotoxigenic Escherichia coli diversity in Bangladesh utilizing genomic epidemiology. Sci Rep 7:3402
Hazen, Tracy H; Daugherty, Sean C; Shetty, Amol C et al. (2017) Transcriptional Variation of Diverse Enteropathogenic Escherichia coli Isolates under Virulence-Inducing Conditions. mSystems 2:
Hazen, Tracy H; Michalski, Jane; Luo, Qingwei et al. (2017) Comparative genomics and transcriptomics of Escherichia coli isolates carrying virulence factors of both enteropathogenic and enterotoxigenic E. coli. Sci Rep 7:3513
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 84:2362-2371
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
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
Lindsay, Brianna; Saha, Debasish; Sanogo, Doh et al. (2015) Association Between Shigella Infection and Diarrhea Varies Based on Location and Age of Children. Am J Trop Med Hyg 93:918-24

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