Escherichia coli O157:H7 (EHEC) is a food-borne pathogen that causes bloody diarrhea and hemolytic uremic syndrome (HUS), a complication of EHEC disease that can lead to kidney failure, throughout the world. EHEC has a very low infectious dose, making it difficult to control epidemiologically. EHEC colonizes the large intestine where it attaches to colonic epithelial cells and causes effacement of microvilli. EHEC also produces Shiga toxin that causes the major symptoms of HUS. In order to successfully colonize the host and establish infection, EHEC must be able to compete with the indigenous microbiota for nutrients. Ethanolamine (EA) is present in the gastrointestinal tract. EHEC uses EA as a nitrogen source, thereby gaining a competitive advantage over the indigenous micriobiota. Importantly, EHEC has co-opted EA as a signal to promote expression of genes involved in host colonization and infection as well as in Shiga toxin production. The transcriptional regulator EutR activates expression of genes that code for EA metabolism, and we determined that EutR promotes expression of EHEC virulence genes. Although EutR is important for EHEC pathogenesis, very little is known concerning the extent of EutR gene regulation in EHEC or how EutR functions to regulate virulence genes.
In Specific Aim 1, we will perform a detailed characterization of the role of EutR in EHEC pathogenesis as well as examine the mechanisms of EutR virulence gene regulation. Interestingly, EHEC responds to EA and modulates virulence gene expression in the eutR mutant strain suggesting that EHEC encodes a second EA sensor.
In Specific Aim 2, we will investigate the roles and mechanisms of EA-dependent, EutR-independent virulence gene regulation in EHEC.
Specific Aim 3 will address how these EA-sensors contribute to EHEC fitness and virulence gene expression during infection. The proposed experimental approaches will achieve a better understanding of mechanisms used by EHEC to activate its virulence genes and may reveal novel aspects of EHEC pathogenesis. Altogether, these data may lead to the development of unique strategies for intervention and/or treatment for EHEC disease.

Public Health Relevance

Escherichia coli O157:H7 is a food-borne pathogen that causes severe bloody diarrhea and life-threatening complications. In order to cause disease, E. coli O157:H7 must compete with harmless microbes in the gut for nutrients. Ethanolamine is present in the gut and serves as a nutrient for E. coli O157:H7. Our research explores how E. coli O157:H7 exploits ethanolamine as a signal to colonize the gut and establish infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Baqar, Shahida
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University of Virginia
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Anderson, Christopher J; Satkovich, John; Köseo?lu, Volkan K et al. (2018) The Ethanolamine Permease EutH Promotes Vacuole Adaptation of Salmonella enterica and Listeria monocytogenes during Macrophage Infection. Infect Immun 86:
Rowley, Carol A; Anderson, Christopher J; Kendall, Melissa M (2018) Ethanolamine Influences Human Commensal Escherichia coli Growth, Gene Expression, and Competition with Enterohemorrhagic E. coli O157:H7. MBio 9:
Anderson, Christopher J; Kendall, Melissa M (2017) Salmonella enterica Serovar Typhimurium Strategies for Host Adaptation. Front Microbiol 8:1983
Santiago, Araceli E; Yan, Michael B; Hazen, Tracy H et al. (2017) The AraC Negative Regulator family modulates the activity of histone-like proteins in pathogenic bacteria. PLoS Pathog 13:e1006545
Anderson, Christopher J; Kendall, Melissa M (2016) Location, location, location. Salmonella senses ethanolamine to gauge distinct host environments and coordinate gene expression. Microb Cell 3:89-91
Luzader, Deborah H; Willsey, Graham G; Wargo, Matthew J et al. (2016) The Type Three Secretion System 2-Encoded Regulator EtrB Modulates Enterohemorrhagic Escherichia coli Virulence Gene Expression. Infect Immun 84:2555-65
Luzader, Deborah H; Kendall, Melissa M (2016) Commensal 'trail of bread crumbs' provide pathogens with a map to the intestinal landscape. Curr Opin Microbiol 29:68-73
Santiago, Araceli E; Yan, Michael B; Tran, Minh et al. (2016) A large family of anti-activators accompanying XylS/AraC family regulatory proteins. Mol Microbiol 101:314-32
McKenney, Elizabeth S; Kendall, Melissa M (2016) Microbiota and pathogen 'pas de deux': setting up and breaking down barriers to intestinal infection. Pathog Dis 74:
Kendall, Melissa M; Sperandio, Vanessa (2016) What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host-Pathogen Associations. MBio 7:e01748

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