Inter-Kingdom Signaling of Stress Hormones: Sensing, Transport and Modulation of Bacterial Physiology

Abstract

Prokaryotes and eukaryotes have coexisted for millions of years. The hormonal communication between microorganisms and their hosts, dubbed inter-kingdom signaling, is a recent field of research. Eukaryotic signals such as hormones, neurotransmitters or immune system molecules have been shown to modulate bacterial physiology. Among them, catecholamines hormones epinephrine/norepinephrine, released during stress and physical effort, or used therapeutically as inotropes have been described to affect bacterial behaviors (i.e., motility, biofilm formation, virulence) of various Gram-negative bacteria (e.g., Escherichia coli, Salmonella enterica serovar Typhimurium, Pseudomonas aeruginosa, Vibrio sp.). More recently, these molecules were also shown to influence the physiology of some Gram-positive bacteria like Enterococcus faecalis. In E. coli and S. enterica, the stress-associated mammalian hormones epinephrine and norepinephrine trigger a signaling cascade by interacting with the QseC histidine sensor kinase protein. No catecholamine sensors have been well described yet in other bacteria. This review aims to provide an up to date report on catecholamine sensors in eukaryotes and prokaryotes, their transport, and known effects on bacteria.

Keywords: bacterial physiology; catecholamines; sensing; stress hormones; transport.

FIGURE 1

Pathway of epinephrine and norepinephrine biosynthesis. Synthesis of catecholamines starts with conversion of L-tyrosine to L-dopa by tyrosine hydroxylase (TH). Then, L-dopa is processed to dopamine by L-aromatic amino acid decarboxylase (AADC), from where norepinephrine is formed by dopamine-β-hydroxylase (DβH). Finally, epinephrine is synthesized by addition of a methyl group to norepinephrine by phenylethanolamine-N-methyltransferase (PNMT). In mammals, catecholamines are synthesized from L-Dopa, obtained from dietary sources (the amino acids tyrosine and phenylalanine).

FIGURE 2

Activating pathways of adrenergic sensors. Catecholamines activate various cellular signal transduction by binding to α 1-, α 2-, and β-adrenoreceptors (yellow). The α1-receptor is coupled with Gq protein, allowing activation of kinase protein C (PKC) and increase of intracellular concentration of Ca2+, through the triphosphate inositol (IP3)/diacylglycerol (DAG) pathway. Activation of this pathway results from the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) in IP3 and DAG thanks to phospholipase C (PLC). α-2 and β-receptors are coupled to Gi and Gs, respectively. In both cases, cAMP (cyclic adenosine monophosphate) is increased or decreased depending on the stimulation (Gs) or inhibition (Gi) of adenylate cyclase (AC), leading to the activation of kinase protein A (PKA). Adapted from Andreis and Singer (2016).

FIGURE 3

Catecholamine sensing and signal transduction in enterohemorrhagic and enteropathogenic E. coli (EHEC/EPEC). QseC is an adrenergic sensor kinase that autophosphorylates on detection of NE, Epi and AI-3 and transfers the phosphate moiety to its cognate response regulator QseB, thereby activating transcription of the flagellar regulon (Clarke et al., 2006). Transcription of genes encoding a second two-component system (QseEF) is sensitive to NE and Epi and is implicated in small RNAs expression (Reading et al., 2009). Kinase activity in QseC is promiscuous and can activate two additional non-cognate response regulators, KdpE and QseF. QseC also activates the locus of enterocyte effacement (LEE), through KdpE, which is inhibited through sRNAs (glmY) that are modulated by QseF. (Adapted from Ellermann and Sperandio, 2020). KdpD, a transmembrane protein showing partial homology with QseC may also act as a catecholamine receptor (Borrel et al., 2019).