Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems

Karavolos, Michail H.; Winzer, Klaus; Williams, Paul; Khan, Coralie

doi:10.1111/mmi.12110

Cited by 89 publications

(95 citation statements)

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“…Quorum-sensing through TCSs is considered an adaptive and auxiliary function of bacteria-one that is critical for virulence, infection, and enhanced fitness but not essential for growth and survival (45). This concept has been strengthened by studies demonstrating that quorum-sensing inhibitors, like LED209, can reduce bacterial virulence without affecting growth (21).…”

Section: Discussionmentioning

confidence: 87%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet −/− Rag2 −/− IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.colitis | Escherichia coli | QseC | antivirulence | gut microbiome

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Section: Discussionmentioning

confidence: 87%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The quorum-sensing kinase QseC has been implicated in NEinduced expression of virulence and motility genes in pathogenic E. coli and S. enterica (4,5). Induction of tynA and feaB transcription by exposure to NE was abolished in the ⌬qseC mutant SP103 (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…However, the effects of NE in enhancing virulence require higher concentrations than those that are predicted to exist in the gut, and in some cases, they appear to be independent of QseC and instead related to the ability of NE to serve as an iron chelator (15). However, both ␣-and ␤-adrenergic receptor antagonists inhibit the responses of enteric bacteria to catecholamines, and receptors other than QseC, including QseE, BasS, and CpxA, have been reported to contribute to the bacterial response to adrenergic signals (5). The current study was undertaken to determine the mechanisms underlying chemotaxis to NE as a first step toward investigating whether chemotaxis contributes to the virulence of enteric bacteria.…”

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confidence: 99%

“…However, the compounds that have been reported as chemoattractants (9) are primarily nutrients: serine and related amino acids, sensed by the chemoreceptor Tsr; aspartate and maltose, sensed by Tar; ribose and galactose, sensed by Trg; and dipeptides and pyrimidines, sensed by Tap. NE has been reported to be an interdomain signaling molecule (5,10,11). NE serves as an inducer of virulence and motility genes in enterohemorrhagic E. coli (EHEC) and in Salmonella enterica (6,10).…”

mentioning

confidence: 99%

“…It has been suggested that norepinephrine (NE), the predominant neurotransmitter of the enteric sympathetic nervous system, promotes growth and virulence of enteric bacteria (1) through signaling via adrenergic receptors located either on intestinal epithelial cells (2) or in the bacteria themselves (3,4). In particular, the bacterial quorum sensor kinase QseC has been implicated in the NE-induced expression of genes whose products are involved in adherence, motility, and pathogenesis (4,5). However, the concentrations of NE required for effective induction of virulence genes, 50 M in one recent study (6), are higher than those that are expected to occur in the intestinal lumen (7,8).…”

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confidence: 99%

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Chemotaxis of Escherichia coli to Norepinephrine (NE) Requires Conversion of NE to 3,4-Dihydroxymandelic Acid

et al. 2014

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Norepinephrine (NE), the primary neurotransmitter of the sympathetic nervous system, has been reported to be a chemoattractant for enterohemorrhagic Escherichia coli (EHEC). Here we show that nonpathogenic E. coli K-12 grown in the presence of 2 M NE is also attracted to NE. Growth with NE induces transcription of genes encoding the tyramine oxidase, TynA, and the aromatic aldehyde dehydrogenase, FeaB, whose respective activities can, in principle, convert NE to 3,4-dihydroxymandelic acid (DHMA). Our results indicate that the apparent attractant response to NE is in fact chemotaxis to DHMA, which was found to be a strong attractant for E. coli. Only strains of E. coli K-12 that produce TynA and FeaB exhibited an attractant response to NE. We demonstrate that DHMA is sensed by the serine chemoreceptor Tsr and that the chemotaxis response requires an intact serine-binding site. The threshold concentration for detection is <5 nM DHMA, and the response is inhibited at DHMA concentrations above 50 M. Cells producing a heterodimeric Tsr receptor containing only one functional serine-binding site still respond like the wild type to low concentrations of DHMA, but their response persists at higher concentrations. We propose that chemotaxis to DHMA generated from NE by bacteria that have already colonized the intestinal epithelium may recruit E. coli and other enteric bacteria that possess a Tsr-like receptor to preferred sites of infection.T he human gastrointestinal (GI) tract harbors an assortment of bacteria, most of which are harmless or helpful commensals. However, infection of the GI tract by pathogenic bacteria can have devastating consequences. It has been suggested that norepinephrine (NE), the predominant neurotransmitter of the enteric sympathetic nervous system, promotes growth and virulence of enteric bacteria (1) through signaling via adrenergic receptors located either on intestinal epithelial cells (2) or in the bacteria themselves (3, 4). In particular, the bacterial quorum sensor kinase QseC has been implicated in the NE-induced expression of genes whose products are involved in adherence, motility, and pathogenesis (4, 5). However, the concentrations of NE required for effective induction of virulence genes, 50 M in one recent study (6), are higher than those that are expected to occur in the intestinal lumen (7,8). Thus, for NE to activate expression of virulence factors, bacteria would have to navigate to regions of the intestinal epithelium that have locally high concentrations of NE. An obvious candidate for directing such migration is chemotaxis.Chemotaxis in Escherichia coli is well understood at the molecular level. However, the compounds that have been reported as chemoattractants (9) are primarily nutrients: serine and related amino acids, sensed by the chemoreceptor Tsr; aspartate and maltose, sensed by Tar; ribose and galactose, sensed by Trg; and dipeptides and pyrimidines, sensed by Tap. NE has been reported to be an interdomain signaling molecule (5, 10, 11). NE serves as an inducer of v...

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2020

Structure and Function of the Bacterial Genome

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Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems

Cited by 89 publications

References 89 publications

QseC inhibition as an antivirulence approach for colitis-associated bacteria

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Chemotaxis of Escherichia coli to Norepinephrine (NE) Requires Conversion of NE to 3,4-Dihydroxymandelic Acid

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