Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut.

Cristiano G Moreira,Matthew K Waldor,Jennifer M Ritchie,Sebastian E Winter,Meredith M Curtis,Regan Russell,Animesh Anand Mishra,David Weinshenker,Vanessa Sperandio,Sanjeev Narayanan

doi:10.1128/mbio.00826-16

Abstract

ABSTRACTEnteric 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.

Highlights

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
The proficiency of EHEC to colonize the intestine of these mice correlates with the severity of disease; the assessment of CFUs of EHEC in the intestine of these animals provides a numeric readout of disease [49, 50]
We have previously shown that an EHEC qseC mutant is attenuated, with a decreased ability to colonize the colon, ileum, and cecum of these animals on day 5 (D5) postinfection [7]

Summary

Introduction

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. C. rodentium has a decreased ability to colonize dopamine ␤-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. This natural murine pathogen, like EHEC, harbors the LEE (see Fig. 3B) and forms AE lesions on the intestine of mice, leading to colonic hyperplasia [51, 52]. We employed EHEC and C. rodentium animal models to investigate the role of epinephrine/norepinephrine and the bacterial adrenergic receptors QseC and QseE in the pathogenesis of noninvasive enteric pathogens

Methods

Results

Conclusion