Bacterial pathogens can sense a variety of physical and chemical niche-specific cues enabling them to physiologically adapt and modulate virulence to survive and cause disease. To enable successful host-pathogen interactions it is increasingly recognised that bacteria must also respond to a diverse range of host effector molecules. The term "microbial endocrinology" was first used to describe the interactions of microbes with the neuroendocrine environment of their host . Catecholamine hormones like adrenaline and noradrenaline are released in the bloodstream and are involved in the regulation of a wide variety of host physiological processes. Current data suggests that catecholamines can induce DNA damage via production of hydroxyl radicals in the presence of iron . More recently, adrenaline was implicated in the production of hydroxyl radicals in rat hepatocytes via an adrenoreceptor-mediated mechanism .
There is evidence that non-neural cells like peripheral human T lymphocytes contain and are able to synthesize catecholamines from normal precursors in physiologic concentrations [4, 5]. Recently, bacterial lipopolysaccharide has been shown to induce production and release of adrenaline and noradrenaline by macrophages and neutrophils . It was therefore suggested that the phagocytic system represents a diffusely expressed adrenergic organ .
Both adrenaline and noradrenaline are present in the gastrointestinal system where they mediate normal gut physiology . During infection, plasma levels of catecholamines rise in an increase previously associated with the onset of infection . There is evidence to suggest that general stress can alter levels of these hormones in the gut and could act as an environmental cue for pathogens [8, 9].
Indeed, catecholamines have been shown to induce both Gram negative and Gram positive bacterial growth via the provision of iron [10–15]. Noradrenaline affects production of the K99 pilus adhesin of enterotoxigenic Escherichia coli and also Shiga toxin in E. coli O157:H7 thus influencing the virulence fitness of these pathogens [16, 17].
Although catecholamines represent a eukaryotic cell signal to mediate a concerted organ function, bacteria utilise a different form of communication mediated by small molecules termed "autoinducers" in a process called "quorum sensing" [18–20]. Briefly, bacteria produce and sense autoinducers (AIs) in a concentration-dependent fashion. Upon achievement of a critical concentration of autoinducer, a signal is generated to regulate processes such as bioluminescence, antibiotic biosynthesis, plasmid conjugation, biofilm formation, DNA uptake competence, sporulation, and virulence [21–23]. Recently, a novel autoinducer, AI-3, produced by E. coli and other Gram negative bacteria was shown to act in synergy with adrenaline and noradrenaline to regulate E. coli genes involved in motility and virulence independently of enterobactin-mediated iron transport . Furthermore, α adrenergic antagonists were able to block these interactions suggesting sensory transduction through common receptors .
In this report we dissect the global effects of adrenaline on the Salmonella enterica serovar Typhimurium (S. Typhimurium) transcriptome. Our data show that approximately 0.6% of the transcriptome of the pathogen is significantly regulated by adrenaline. Most of the genes affected represent those involved in transport but we also see alterations in genes encoding proteins of unknown functions. We also notice changes in levels of regulators and signal transduction genes.
The major feature of the S. Typhimurium adrenaline response is the upregulation of genes involved in metal homeostasis and oxidative stress. Prompted by the transcriptomic data we investigated the expression of the manganese superoxide dismutase (sodA), and the regulators of iron homeostasis (fur) and oxidative stress (oxyR). Our evidence suggests that adrenaline provides an environmental cue to alert S. Typhimurium against impending macrophage-derived peroxide stress as shown by the reduced ability of S. Typhimurium lacking OxyR to survive in the presence of adrenaline.
Furthermore we identified a downregulation of the pmrHFIJKLM operon which encodes a well characterised lipid A-modification system that provides resistance to the cationic antimicrobial peptide polymyxin B. We investigated the expression of the pmr locus and suggest adrenaline-mediated reduction in antimicrobial peptide resistance is mediated by the BasSR two component signal transduction system.
The fact that adrenaline provides an environmental cue that alerts the bacterial defences against oxidative stress as well as acting in favour of the host by inducing a reduction in bacterial antimicrobial peptide resistance is a unique combination. This finding represents a novel insight concerning the role of hormones in pathogen-host interactions.