To successfully colonize and establish themselves in the gastrointestinal (GI) tract, enteric pathogens must sense and respond to several microbiota and host derived signals to properly regulate expression of their virulence repertoire. An important signal within the GI tract is the host neurotransmitter norepinephrine (NE) and/or epinephrine (Epi), which have important functions in intestinal physiology. There is also an important relationship between neurotransmitters and the microbiota, because it modulates the levels of active Epi and NE in the gut lumen. The host conjugates Epi/NE to glucuronate to inactivate it. The microbiota encodes glucuronidases (encoded by the uidA gene) that deconjugate glucuronate from Epi/NE, increasing the levels of free biologically active Epi/NE in the lumen. We identified the first two bacterial adrenergic receptors, QseC and QseE. The enteric pathogen enterohemorrhagic E. coli (EHEC), exploits adrenergic signaling through QseC and QseE to carefully regulate expression of its virulence genes to promote optimal colonization of the gut. Importantly, EHEC virulence gene regulation intersects with the ability to sense glucuronate, linking deglucuronidation of Epi/NE by the microbiota to Epi/NE sensing at another level of inter- kingdom signaling. We identified ExuR, the sensor for glucoronate, as an important regulator of EHEC virulence gene expression. The linking of Epi/NE sensing through QseC and QseE, with glucuronate sensing through ExuR, ensures the precise control of virulence gene expression by EHEC. Indeed, Citrobacter rodentium (extensively used as a surrogate EHEC model for murine infections) qseC, qseE and exuR mutants are attenuated for murine infection, highlighting the important role of this signaling system in EHEC pathogenesis. Another neurotransmitter system, the endocannabinoid system is also intertwined with the gut microbiota. The endocannabinoid 2-Arachidonoylglycerol (2-AG) is sensed through QseC, preventing QseC function, and decreasing expression of virulence genes in EHEC and C. rodentium. Moreover, Epi and 2-AG antagonize each other at the level of QseC sensing. The levels of 2AG decrease from the small intestine to the colon, oppositely from the levels of Epi/NE. Given that EHEC colonizes the colon, the interplay between the adrenergic and endocannabinoid systems, likely has a key function in the biogeography of this pathogen within the GI tract. Accordingly the specific aims of this proposal are:
Specific Aim 1 : Investigate the relationship among the adrenergic and glucuronate signals in EHEC pathogenesis.
Specific Aim 2 : Investigate the role of the endocannabinoid system in EHEC pathogenesis. .

Public Health Relevance

The goal of this project is to investigate how different host neurotransmitters impact the balance among microbiota-pathogen-host interactions. We will assess how the stress hormones epinephrine and norepinephrine have their impact on enterohemorrhagic E. coli (EHEC) virulence gene regulation counteracted by an endocannabinoid. We will also investigate how the microbiota alters the availability of the active form of these neurotransmitters in the gut.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Baqar, Shahida
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Cameron, Elizabeth A; Curtis, Meredith M; Kumar, Aman et al. (2018) Microbiota and Pathogen Proteases Modulate Type III Secretion Activity in Enterohemorrhagic Escherichia coli. MBio 9:
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:
Sperandio, Vanessa (2018) Pathogens' adaptation to the human host. Proc Natl Acad Sci U S A 115:9342-9343
Romão, Fabiano Teodoro; Hernandes, Rodrigo Tavanelli; Ooka, Tadasuke et al. (2018) Complete Genome Sequence of Escherichia albertii Strain 1551-2, a Potential Extracellular and Intracellular Pathogen. Genome Announc 6:
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
Hernandez-Doria, Juan D; Sperandio, Vanessa (2018) Bacteriophage Transcription Factor Cro Regulates Virulence Gene Expression in Enterohemorrhagic Escherichia coli. Cell Host Microbe 23:607-617.e6
Yamamoto, Denise; Hernandes, Rodrigo T; Liberatore, Ana Maria A et al. (2017) Escherichia albertii, a novel human enteropathogen, colonizes rat enterocytes and translocates to extra-intestinal sites. PLoS One 12:e0171385
Lustri, Bruna C; Sperandio, Vanessa; Moreira, Cristiano G (2017) Bacterial Chat: Intestinal Metabolites and Signals in Host-Microbiota-Pathogen Interactions. Infect Immun 85:
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:

Showing the most recent 10 out of 18 publications