Quorum sensing is a cell-to-cell signaling mechanism in which bacteria respond to hormone-like molecules called autoinducers (AIs). The AI-3 quorum-sensing system is also involved in interkingdom signaling with the eukaryotic hormones epinephrine͞ norepinephrine. This signaling activates transcription of virulence genes in enterohemorrhagic Escherichia coli O157:H7. However, this signaling system has never been shown to be involved in virulence in vivo, and the bacterial receptor for these signals had not been identified. Here, we show that the QseC sensor kinase is a bacterial receptor for the host epinephrine͞norepinephrine and the AI-3 produced by the gastrointestinal microbial flora. We also found that an ␣-adrenergic antagonist can specifically block the QseC response to these signals. Furthermore, we demonstrated that a qseC mutant is attenuated for virulence in a rabbit animal model, underscoring the importance of this signaling system in virulence in vivo. Finally, an in silico search found that the periplasmic sensing domain of QseC is conserved among several bacterial species. Thus, QseC is a bacterial adrenergic receptor that activates virulence genes in response to interkingdom cross-signaling. We anticipate that these studies will be a starting point in understanding bacterial-host hormone signaling at the biochemical level. Given the role that this system plays in bacterial virulence, further characterization of this unique signaling mechanism may be important for developing novel classes of antimicrobials.AI-3 ͉ enterohemorrhagic Escherichia coli ͉ epinephrine ͉ quorum sensing ͉ two-component systems

Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.A key challenge for medicine is to develop new drugs against pathogens that are resistant to current antimicrobial agents (1,2). A promising strategy is to identify agents that inhibit microbial virulence without inhibiting growth, because these present less selective pressure for the generation of resistance (3-5). Many bacterial pathogens recognize the host environment by sensing and responding to the host adrenergic signaling molecules epinephrine and norepinephrine (NE) in order to promote the expression of virulence factors (6,7). These pathogens appear to use the same membrane-embedded sensor histidine kinase, QseC (7), to recognize both host-derived adrenergic signals and the bacterial aromatic signal autoinducer-3 (AI-3) to activate their virulence genes (5,6). Upon sensing any of these signaling molecules, QseC autophosphorylates and subsequently phosphorylates a transcription factor, QseB (Fig. 1A) (7), which initiates a relay to a complex regulatory cascade and leads to the transcription of key virulence genes (Fig. 1B) (5-8).QseC homologs are present in at least 25 important human and plant pathogens (table S1), and qseC mutants of enterohemorrhagic Escherichia coli (EHEC) (Fig. 1C and fig. S1) (7), Salmonella typhimurium ( Fig. 2A) (8), and Francisella tularensis (9) are attenuated in infected †To whom correspondence should be addressed.

Microorganisms and their hosts communicate with each other through an array of hormonal signals. This cross-kingdom cell-to-cell signalling involves small molecules, such as hormones that are produced by eukaryotes and hormone-like chemicals that are produced by bacteria. Cell-to-cell signalling between bacteria, usually referred to as quorum sensing, was initially described as a means by which bacteria achieve signalling in microbial communities to coordinate gene expression within a population. Recent evidence shows, however, that quorum-sensing signalling is not restricted to bacterial cell-to-cell communication, but also allows communication between microorganisms and their hosts.Prokaryotes and eukaryotes have coexisted for millions of years. It is estimated that humans have 10 13 human cells and 10 14 bacterial cells (comprising the endogenous bacterial flora). Eukaryotes have a variable relationship with prokaryotes, and these interactions can be either beneficial or detrimental. Humans maintain a symbiotic association with their intestinal microbial flora, which is crucial for nutrient assimilation and development of the innate immune system 1 . These mutually beneficial associations are possible because microorganisms and mammals can communicate with each other through various hormone and hormone-like chemical compounds. These signals, however, can be 'hijacked' by bacterial pathogens to activate their virulence genes.The hormonal communication between microorganisms and their hosts, dubbed inter-kingdom signalling, is a recent field of research. This field evolved from the initial observation that bacteria can communicate with each other through hormone-like signals 2 , a process that was later named quorum sensing (QS) 3 . This field expanded with the realization that these bacterial signals can modulate mammalian cell-signal transduction 4 and that host hormones can crosssignal with QS signals to modulate bacterial gene expression 5 .In this Review, we discuss several mechanisms that are used for hormonal communication between micro-organisms and their hosts. Owing to space constraints, we mainly consider pathogenic interactions. We focus primarily on acyl-homoserine lactones (AHLs) and aromatic (autoinducer (AI)-3) signals, because of the wealth of reports that link these signals to interkingdom communication, but it is worth noting that bacteria use an array of additional chemical