Enterohemorrhagic E. coli (EHEC) serotype O157:H7 is responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome throughout the world. The main reservoir for EHEC is cattle herds. EHEC colonization of cattle has been shown to require a functional locus of enterocyte effacement (LEE) region, involved in intestinal adhesion, and formation of lesions on enterocytes named attaching and effacing (AE) lesions, as well as a functional SdiA transcription factor. SdiA is a quorum sensing transcription factor that requires its autoinducer, an acyl-homoserine lactone (AHL) for proper folding and function. EHEC harbors SdiA, but does not produce an AHL autoinducer, consequently having to sense AHLs produced by other species of bacteria in the environment. These observations, combined with reports showing that AHLs are prominent within cattle rumen, suggest an important role for SdiA- AHL mediated regulation of EHEC genes necessary for colonization of the bovine gastrointestinal (GI) tract. We demonstrated that both synthetic AHLs, as well as AHLs extracted from cattle rumen repress expression of the LEE genes. However, the role of diet in modulating AHL levels within the rumen, and their correlation with EHEC shedding remain poorly understood. Furthermore, the mechanisms by which SdiA regulates transcription are still unknown. Finally, the distribution of an sdiA mutant within the intestinal tract of cattle, as well as a definitive reason underlying its attenuation remains to be established. Accordingly the Specific Aims of this study are:
Specific Aim 1 : To assess the presence of AHLs in rumen samples from cattle, as well as their correlation with diet and EHEC shedding.
Specific Aim 2 : Determine the molecular mechanisms of SdiA-dependent gene regulation.
Specific Aim 3 : Characterize the distribution of an sdiA mutant within the bovine intestine, and better define the basis for this mutant's diminished ability to colonize cattle.

Public Health Relevance

Enterohemorrhagic E.coli (EHEC) serotype O157:H7 is the agent responsible for outbreaks of bloody diarrhea throughout the world. The main reservoir for EHEC is cattle herds. Consequently, diminishing cattle colonization and shedding of EHEC is of great interest to human health. In this grant proposal, we aim to understand how a signaling mechanism between bacterial cells through a small molecule called acyl-homoserine lactone, which is present in the rumen of cattle, controls expression of EHEC genes necessary for virulence and colonization of the bovine intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077613-05
Application #
8417744
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Baqar, Shahida
Project Start
2009-02-13
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$355,343
Indirect Cost
$105,028
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Cameron, Elizabeth A; Gruber, Charley C; Ritchie, Jennifer M et al. (2018) The QseG Lipoprotein Impacts the Virulence of Enterohemorrhagic Escherichia coli and Citrobacter rodentium and Regulates Flagellar Phase Variation in Salmonella enterica Serovar Typhimurium. Infect Immun 86:
Pifer, Reed; Russell, Regan M; Kumar, Aman et al. (2018) Redox, amino acid, and fatty acid metabolism intersect with bacterial virulence in the gut. Proc Natl Acad Sci U S A 115:E10712-E10719
Carlson-Banning, Kimberly M; Sperandio, Vanessa (2018) Enterohemorrhagic Escherichia coli outwits hosts through sensing small molecules. Curr Opin Microbiol 41:83-88
Parker, Christopher T; Russell, Regan; Njoroge, Jacqueline W et al. (2017) Genetic and Mechanistic Analyses of the Periplasmic Domain of the Enterohemorrhagic Escherichia coli QseC Histidine Sensor Kinase. J Bacteriol 199:
Bäumler, Andreas J; Sperandio, Vanessa (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85-93
Kendall, Melissa M; Sperandio, Vanessa (2016) What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host-Pathogen Associations. MBio 7:e01748
Cameron, Elizabeth A; Sperandio, Vanessa (2015) Frenemies: Signaling and Nutritional Integration in Pathogen-Microbiota-Host Interactions. Cell Host Microbe 18:275-84
Nguyen, Y; Nguyen, Nam X; Rogers, Jamie L et al. (2015) Structural and mechanistic roles of novel chemical ligands on the SdiA quorum-sensing transcription regulator. MBio 6:
Sperandio, Vanessa (2015) Bacterial Reductionism: Host Thiols Enhance Virulence. Cell Host Microbe 18:7-8
Curtis, Meredith M; Hu, Zeping; Klimko, Claire et al. (2014) The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape. Cell Host Microbe 16:759-69

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