Gastrointestinal infections claim the lives of 2-3 million children annually. Interim data from a Global Enteric Multicenter Study indicate that a disporportionate number of deaths among children is associated with infections due to enteropathogenic E. coli (EPEC) and Shigella spp. In this project we will investigate the contribution to pathogenesis of specific factors produced by EPEC and Shigella that are associated with severe disease and we will discover new such factors in EPEC. We will determine the genome sequence of 20 EPEC strains recently isolated from children who succumbed to diarrhea, 20 strains from children with non-lethal sypmptomatic infection and 20 strains from asymptomatic control children. We will specifically seek new genetic loci that are associated with symptomatic infection and with lethal outcome. We will determine the host cell targets and mechanisms of action of two proteins, NIeB and NIeE, that are secreted by EPEC and injected into host cells and that have been associated in previous studies with increased virulence in humans. We will also determine the contributions to pathgenesis of novel EPEC genetic loci associated with virulence identified by the above genomic sequencing. And we will determine the target and mechanism of action of a protein known as ShET2 that is produced and secreted by both EPEC and Shigella, associated with increased virulence in human EPEC infection, and has been proposed but not proven to be injected into host cells. Together, these experiments will yield an unprecidented amount of data on the genetic basis of EPEC pathogenesis, uncover mechanisms of action of virulence factors from EPEC and Shigella, and in particular identify novel loci associated with deadly infections. These data will serve as an extremely valuable resource for new initiatives to prevent and treat severe enteric infections.

Public Health Relevance

Microbes that cause diarrhea kill 2-3 million children each year. We found that certain types of bacteria are particulariy deadly. We will identify all of 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 but did not die or who had no symptoms. Determining how these contribute to disease will lead to new preventative and treatment options.

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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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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