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

Abstract

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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