Cited by 157Escherichia coli research studiesBacterial Genetics and BiotechnologyEnterobacteriaceae and Cronobacter Research

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Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut

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Moreira, Cristiano G., Russell, Regan, Mishra, Animesh Anand, Narayanan, Sanjeev, Ritchie, Jennifer M., Waldor, Matthew K., Curtis, Meredith M., Winter, Sebastian E., Weinshenker, David, Sperandio, Vanessa·2016·mBio

DOI 10.1128/mbio.00826-16PMC PMC4959670

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Abstract

UNLABELLED: 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.

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FIG 1 EHEC infection in infant rabbits at day 2 postinfection. Data depict CFUs of EHEC in the ileum (A), cecum (B), colon (C), and stool (D). *, P < 0.05; ***, P < 0.001.CC BY · PubMed Central

FIG 2 EHEC infection in infant rabbits at day 5 postinfection. Data depict CFUs of EHEC in the ileum (A), cecum (B), colon (C), and stool (D). **, P < 0.01; ***, P < 0.001.CC BY · PubMed Central

FIG 3 Virulence gene regulation in C. rodentium by epinephrine and norepinephrine. (A) Scheme of recognition by the QseC and QseE bacterial adrenergic receptors of their signals. QseC senses epinephrine (Epi) and norepinephrine (NE), and QseE senses Epi, NE, sulfate (SO4), and phosphate (PO4). (B) Homology comparisons among the LEE regions of EHEC, enteropathogenic E. coli (EPEC), and C. rodentium. (C) Expression of genes within the QseC regulon, the LEE, effectors, and adhesins in the absence and presence of 50 µM epinephrine or norepinephrine in DMEM (OD600 of 0.7 at 37°C).CC BY · PubMed Central

FIG 4 C. rodentium murine infections in C3H/HeJ mice. (A) Survival curves of animals infected with different doses of the WT strain and the qseC mutant with an infectious dose of 109 CFU. (B) Survival curves of animals infected with different doses of the WT strain and the qseC mutant with an infectious dose of 108 CFU. (C) Survival curves of animals infected with different doses of the WT strain and the qseC mutant with an infectious dose of 105 CFU. (D) Survival curves of animals infected with the WT strain and the qseE mutant (P < 0.02). (E) Colon weights of animals infected with the WT strain and the qseE mutant; PBS is the negative control.CC BY · PubMed Central

FIG 5 Microbiota composition of Dbh+/− and Dbh−/− mice infected with WT, ΔqseC, ΔqseE, and ΔqseEC C. rodentium at day 1 (A) and day 7 (B) postinfection. PBS mice were used as negative controls.CC BY · PubMed Central

FIG 6 CFUs in stools of Dbh+/− and Dbh−/− mice infected with WT, ΔqseC, ΔqseE, and ΔqseEC C. rodentium on days 1 to 7. PBS mice were used as negative controls. *, P < 0.0001.CC BY · PubMed Central

FIG 7 Expression of the LEE espA and tir genes, measured by qRT-PCR, in stools of Dbh+/− and Dbh−/− mice infected with WT, ΔqseC, ΔqseE, and ΔqseEC C. rodentium on day 7 postinfection. PBS mice were used as negative controls. *, P < 0.05; **, P < 0.0001.CC BY · PubMed Central

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Authors: Moreira, C. G., Russell, R., Mishra, A. A., Narayanan, S., Ritchie, J. M., Waldor, M. K., Curtis, M. M., Winter, S. E., Weinshenker, D., & Sperandio, V.
Affiliations: The University of Texas Southwestern Medical Center (US)
Kansas State University (US)
University of Surrey (GB)
Brigham and Women's Hospital (US)
Emory University (US)
Corresponding author: Sperandio, Vanessa
ORCID: Moreira, Cristiano G.
Mishra, Animesh Anand
Narayanan, Sanjeev
Ritchie, Jennifer M.
Waldor, Matthew K.
Winter, Sebastian E.
Weinshenker, David
Sperandio, Vanessa
Venue: mBio
Publisher: American Society for Microbiology
Published: 2016-07-06
Volume: 7
Issue: 3
ISSN: 2150-7511 (ISSN-L)
2161-2129
DOI: 10.1128/mbio.00826-16
PMC: PMC4959670
OpenAlex: W2411358133
Cited by: 157
References: 81
Citations by year: 2026: 21 · 2025: 20 · 2024: 16 · 2023: 23 · 2022: 17 · 2021: 11 · 2020: 9 · 2019: 16 · 2018: 11 · 2017: 8 · 2016: 3
FWCI: 12.19
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
journals.asm.org/non-commercial-tdm-license (tdm)
Locations: mBio (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
K-State Research Exchange (Kansas State University) (submittedVersion, cc-by)
Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Open Research (University of Surrey) (submittedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
UNESP Institutional Repository (São Paulo State University) (submittedVersion)
Funders: HHS | National Institutes of Health (T32 AI7520)
HHS | NIH | National Institute of Allergy and Infectious Diseases (AI101472, AI05135, AI053067)
Topics: Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Life Sciences › Immunology and Microbiology › Microbiology › Enterobacteriaceae and Cronobacter Research
Keywords: QseC, epinephrine, norepinephrine, enteric pathogens, Citrobacter rodentium, enterohemorrhagic Escherichia coli, locus of enterocyte effacement, virulence gene regulation, dopamine beta-hydroxylase, intestinal colonization, attaching and effacing lesions, host-pathogen interaction
MeSH terms: Animals, Dopamine beta-Hydroxylase, Enterobacteriaceae Infections, Epinephrine, Escherichia coli Infections, Genes, Bacterial, Norepinephrine, Phosphoproteins, Receptors, Adrenergic, Vasoconstrictor Agents, Virulence, Gene Expression Regulation, Bacterial, Mice, Knockout, Enterocytes, Escherichia coli Proteins, Gastrointestinal Tract, Citrobacter rodentium, Mice, Enterohemorrhagic Escherichia coli, Host-Pathogen Interactions

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Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut

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