# Quorum Sensing Regulation of EHEC Virulence Genes

> **NIH NIH R37** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $465,045

## Abstract

Project Summary/Abstract
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.
.

## Key facts

- **NIH application ID:** 10596309
- **Project number:** 7R37AI053067-21
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** VANESSA SPERANDIO
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $465,045
- **Award type:** 7
- **Project period:** 2003-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596309

## Citation

> US National Institutes of Health, RePORTER application 10596309, Quorum Sensing Regulation of EHEC Virulence Genes (7R37AI053067-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10596309. Licensed CC0.

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