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The Serotonin Neurotransmitter Modulates Virulence of Enteric Pathogens.

ABSTRACT: 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.

SUBMITTER: Kumar A

PROVIDER: S-EPMC7351610 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Serotonin Neurotransmitter Modulates Virulence of Enteric Pathogens.

Kumar Aman A Russell Regan M RM Pifer Reed R Menezes-Garcia Zelia Z Cuesta Santiago S Narayanan Sanjeev S MacMillan John B JB Sperandio Vanessa V

Cell host & microbe 20200609 1

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 i ...[more]

PMID: 32521224

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Project description:Enteric pathogens such as enterohemorrhagic E. coli (EHEC) and its surrogate murine model Citrobacter rodentium sense indole levels within the gut to navigate its biogeography and modulate virulence gene expression. Indole is a microbiota-derived signal that is more abundant in the intestinal lumen, with its concentration decreasing at the epithelial lining where it is absorbed. E. coli, but not C. rodentium, produces endogenous indole because it harbors the tnaA gene. Microbiota-derived exogenous indole is sensed by the CpxAR two-component system, where CpxA is a membrane-bound histidine-sensor-kinase (HK) and CpxR is a response regulator (RR). Indole inhibits CpxAR function leading to decreased expression of the locus of enterocyte effacement (LEE) pathogenicity island, which is essential for these pathogens to form lesions on enterocytes. In our transcriptome studies comparing wild-type (WT) EHEC and ΔtnaA ± indole, one of the most upregulated genes by indole is ygeV, which is a predicted orphan RR. Because of the role YgeV plays in the indole signaling cascade, we renamed this gene indole sensing regulator (isrR). In the absence of endogenous indole, IsrR activates LEE gene expression. IsrR only responds to endogenous indole, with exogenous indole still blocking virulence gene expression independently from IsrR. Notably, a C. rodentium isrR mutant is attenuated for murine infection, depicting delayed death, lower intestinal colonization, and LEE gene expression. IsrR aids in discriminating between microbiota-derived (exogenous) and endogenous self-produced indole in fine-tuning virulence gene expression by enteric pathogens in the intestine. IMPORTANCE Enteric pathogens sense the complex intestinal chemistry to find a suitable colonization niche. The microbiota plays an important part in shaping this chemistry. Here we show that the abundant microbiota-derived exogenous signal indole impacts host-pathogen interactions by allowing enteric pathogens to discriminate between the luminal environment, where expression of virulence genes is an unnecessary energy burden, from the epithelial surface, where this gene expression is needed for host colonization. We describe a new signaling node through the regulator IsrR that allows for this shift. These findings establish a mechanism through which pathogens discriminate from self- and microbiota-derived signaling to establish infection.

Project description: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. 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.

Dataset Information

The Serotonin Neurotransmitter Modulates Virulence of Enteric Pathogens.

Publications

The Serotonin Neurotransmitter Modulates Virulence of Enteric Pathogens.

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