Enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, which is largely used as a surrogate EHEC model for murine
infections, are exposed to several host
neurotransmitters in the gut. An important chemical exchange within the gut involves the
neurotransmitters epinephrine and/or
norepinephrine, extensively reported to increase virulence gene expression in EHEC, acting through two bacterial
adrenergic sensors: QseC and QseE. However, EHEC is unable to establish itself and cause its hallmark lesions, attaching and effacing (AE) lesions, on murine enterocytes. To address the role of these
neurotransmitters during enteric
infection, we employed C. rodentium Both EHEC and C. rodentium harbor the locus of enterocyte effacement (LEE) that is necessary for AE lesion formation. Here we show that expression of the LEE, as well as that of other virulence genes in C. rodentium, is also activated by
epinephrine and/or
norepinephrine. Both QseC and QseE are required for LEE gene activation in C. rodentium, and the qseC and qseE mutants are attenuated for murine
infection. C. rodentium has a decreased ability to colonize
dopamine β-
hydroxylase knockout (Dbh(-/-)) mice, which do not produce
epinephrine and
norepinephrine. Both
adrenergic sensors are required for C. rodentium to sense these
neurotransmitters and activate the LEE genes during
infection. These data indicate that
epinephrine and
norepinephrine are sensed by bacterial
adrenergic receptors during enteric
infection to promote activation of their virulence repertoire. This is the first report of the role of these
neurotransmitters during mammalian gastrointestinal (GI)
infection by a noninvasive pathogen.
IMPORTANCE: The
epinephrine and
norepinephrine neurotransmitters play important roles in gut physiology and motility. Of note,
epinephrine and
norepinephrine play a central role in stress responses in mammals, and stress has profound effects on GI function. Bacterial enteric pathogens exploit these
neurotransmitters as signals to coordinate the regulation of their virulence genes. The bacterial QseC and QseE
adrenergic sensors are at the center of this regulatory cascade. C. rodentium is a noninvasive murine pathogen with a colonization mechanism similar to that of EHEC, enabling the investigation of host signals in mice. The presence of these
neurotransmitters in the gut is necessary for C. rodentium to fully activate its virulence program, in a QseC/QseE-dependent manner, to successfully colonize its murine host. Our study data provide the first example of
epinephrine and
norepinephrine signaling within the gut to stimulate
infection by a bacterial pathogen in a natural animal
infection.