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 - 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
UR - http://www.scopus.com/inward/record.url?scp=85088064372&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088064372&partnerID=8YFLogxK
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 -