Diarrheal diseases are a major killer of children under the age of 5. These infections infections represent a balance between the microbe and the host. Host responses to enteric infections include those seen in the intestinal epithelium and in the mucosal/systemic immune system. This project will examine both types of responses using mouse intestinal tissue and human clinical specimens.
Specific Aim 1 will characterize the response of mouse epithelial tissue mounted in Ussing chambers and microsnapwells to infection with Shigella and enteropathogenic E. coli (EPEC) with particular emphasis on intestinal barrier function, short circuit current, and epithelial cytokine production. Several isogenic mutants defective in specific virulence factors will be tested to determine the contribution of these factors to the responses seen. In contrast to Aim 1, which will employ wild type mice and various bacterial mutants, Specific Aim 2 will employ wild type bacteria and various mutant mouse strains to establish the role of specific pattern recognition receptors (PRRs) in the intestinal mucosal response to Shigella and EPEC. Intestinal tissue will be isolated from wild type and knock out mice deficient in MyD88, TLR4, TLR5, Nodi, Nod2, PAR2 , or mast cells and exposed ex vivo to Shigella and EPEC. Comparison of the intestinal mucosal function and immune responses in the different mouse lines will characterize the role of these PRRs in infections due to EPEC and Shigella.
Specific Aim 3 will examine adaptive immunity and immunological markers in the Gl tract that are associated with Shigella and EPEC infection in children from endemic countries. Stool specimens from children with documented Shigella and EPEC infections in the GEMS study will be analyzed for pathogen specific adaptive responses including sIgA, IgA, and IgG specific for Shigella and EPEC antigens. Fecal cytokines and inflammatory molecules will also be analyzed and correlations sought with clinical outcomes.

Public Health Relevance

Microbes that cause diarrhea kill 2 - million children each year. These intestinal infections represent a balance between the microbe and the host. This project will examine the effects of the microbe on the host, particulariy in the gastrointestinal tract. Determining the exact processes that are occuring the gastrointestinal tract can 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 (M2))
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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:
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
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; 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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