TY - JOUR
T1 - The Serotonin Neurotransmitter Modulates Virulence of Enteric Pathogens
AU - Kumar, Aman
AU - Russell, Regan M.
AU - Pifer, Reed
AU - Menezes-Garcia, Zelia
AU - Cuesta, Santiago
AU - Narayanan, Sanjeev
AU - MacMillan, John B.
AU - Sperandio, Vanessa
N1 - Funding Information:
We thank Sebastian Winter at UT Southwestern for comments. We thank Noelle Williams, Hamid Baniasadi, and Jessica Kilgore from the UT Southwestern Pharmacology Core facility for their help with the serotonin measurements. This work was supported by the National Institute of Health (NIH) grants AI053067 and AI114511. R.P. was supported through NIH training grant 5 T32 AI7520-14. A.K. and R.M.R. designed and conducted experiments; A.K. analyzed data and wrote the paper; R.P. and S.C. conducted experiments; S. N. and Z.M.G. scored pathology; J.B.M. measured serotonin levels in the intestinal lumen; V.S. conceived the project, designed experiments, and wrote the paper;, The authors declare no competing interests.
Funding Information:
We thank Sebastian Winter at UT Southwestern for comments. We thank Noelle Williams, Hamid Baniasadi, and Jessica Kilgore from the UT Southwestern Pharmacology Core facility for their help with the serotonin measurements. This work was supported by the National Institute of Health (NIH) grants AI053067 and AI114511 . R.P. was supported through NIH training grant 5 T32 AI7520-14 .
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/7/8
Y1 - 2020/7/8
N2 - The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.
AB - The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.
KW - CpxA
KW - enteric infections
KW - enterohemorrhagic E. coli (EHEC)
KW - inter-kingdom signaling
KW - serotonin
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U2 - 10.1016/j.chom.2020.05.004
DO - 10.1016/j.chom.2020.05.004
M3 - Article
C2 - 32521224
AN - SCOPUS:85088064372
SN - 1931-3128
VL - 28
SP - 41-53.e8
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -