Enterohemorrhagic E. coli (EHEC) O157:H7 causes bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. EHEC has a very low infectious dose, making it difficult to control epidemiologically. EHEC colonizes the large intestine where it causes attaching and effacing (AE) lesions, and also produces Shiga toxins (Stx) that are responsible for the major symptoms of HUS. We recently reported that EHEC senses three signals to activate transcription of virulence genes: a bacterial aromatic autoinducer (AI-3) produced by the normal gastrointestinal flora, and the hormones epinephrine/norepinephrine produced by the host. These signals are detected by membrane bound sensor kinases that subsequently relay this information to a complex regulatory cascade to activate transcription of virulence genes. We have identified several members of this signaling cascade: the QseBC and QseEF two-component systems, and the QseA and QseD LysR-like regulators. However, many aspects of this regulatory cascade, which are crucial for EHEC virulence, remain poorly understood. This proposal represents a comprehensive effort to study the AI-3/epinephrine/norepinephrine signaling cascade, responsible for virulence gene regulation in EHEC.
In Specific Aim 1, we will perform a detailed characterization of the QseBC regulon to map this complex regulatory network.
In Specific Aim 2, we will characterize the protein-protein interactions between the QseA and QseD LysR-like regulators and their effect on gene regulation.
Specific Aim 3 is designed to characterize the role of the novel QseEF two-component system in EHEC pathogenesis. The proposed experimental approaches will achieve a better understanding of the sensory events by which EHEC responds to activate its virulence genes, and may lead to the identification of other virulence genes and novel targets for the potential development of more effective intervention strategies for EHEC disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI053067-09
Application #
7996624
Study Section
Special Emphasis Panel (ZRG1-BACP-B (09))
Program Officer
Baqar, Shahida
Project Start
2002-12-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
9
Fiscal Year
2011
Total Cost
$452,016
Indirect Cost
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
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:
Carlson-Banning, Kimberly M; Sperandio, Vanessa (2017) Enterohemorrhagic Escherichia coli outwits hosts through sensing small molecules. Curr Opin Microbiol 41:83-88
Moreira, Cristiano G; Russell, Regan; Mishra, Animesh Anand et al. (2016) Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut. MBio 7:
Kendall, Melissa M; Sperandio, Vanessa (2016) What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host-Pathogen Associations. MBio 7:e01748
Carlson-Banning, Kimberly M; Sperandio, Vanessa (2016) Catabolite and Oxygen Regulation of Enterohemorrhagic Escherichia coli Virulence. MBio 7:
Bäumler, Andreas J; Sperandio, Vanessa (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85-93
Cameron, Elizabeth A; Sperandio, Vanessa (2015) Frenemies: Signaling and Nutritional Integration in Pathogen-Microbiota-Host Interactions. Cell Host Microbe 18:275-84
Pacheco, Alline R; Sperandio, Vanessa (2015) Enteric Pathogens Exploit the Microbiota-generated Nutritional Environment of the Gut. Microbiol Spectr 3:
Gruber, Charley C; Sperandio, Vanessa (2015) Global analysis of posttranscriptional regulation by GlmY and GlmZ in enterohemorrhagic Escherichia coli O157:H7. Infect Immun 83:1286-95
de Paiva, Jacqueline Boldrin; Leite, Janaína Luisa; da Silva, Livia Pilatti Mendes et al. (2015) Influence of the major nitrite transporter NirC on the virulence of a Swollen Head Syndrome avian pathogenic E. coli (APEC) strain. Vet Microbiol 175:123-31

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