Chemosensation of Bacterial Secondary Metabolites Modulates Neuroendocrine Signaling and Behavior of C. elegans

Abstract

Summary Discrimination among pathogenic and beneficial microbes is essential for host organism immunity and homeostasis. Here, we show that chemosensory detection of two secondary metabolites produced by Pseudomonas aeruginosa modulates a neuroendocrine signaling pathway that promotes avoidance behavior in the simple animal host Caenorhabditis elegans. Secondary metabolites phenazine-1-carboxamide and pyochelin activate a G protein-signaling pathway in the ASJ chemosensory neuron pair that induces expression of the neuromodulator DAF-7/TGF-β. DAF-7, in turn, activates a canonical TGF-β signaling pathway in adjacent interneurons to modulate aerotaxis behavior and promote avoidance of pathogenic P. aeruginosa. Our data provide a chemical, genetic, and neuronal basis for how the behavior and physiology of a simple animal host can be modified by the microbial environment, and suggest that secondary metabolites produced by microbes may provide environmental cues that contribute to pathogen recognition and host survival.

Distinct Roles of Sensory Neurons in Mediating Pathogen Avoidance and Neuropeptide-Dependent Immune Regulation

“…In addition, there are synaptic connections between ASH and ASI neurons, suggesting that these two neurons might work collaboratively to coordinate behavior, development, energy consumption, and immunity in response to danger signals from the environment such as pathogenic bacteria (Figure 4G). Other amphid sensory neurons have also been shown to control pathogen avoidance behavior: AWB neurons are responsible for the avoidance of S. marcescens (Pradel et al, 2007), and ASJ neurons are able to detect the secondary metabolites of P. aeruginosa , which induces the cell-autonomous expression of DAF-7 to control pathogen avoidance behavior through a canonical TGF-β signaling (Meisel et al, 2014). The lack-of-avoidance phenotype of daf-7 mutant could be fully rescued by expressing daf-7 in either ASJ neurons or ASI neurons.…”

DAF-tly Depart Stinky Situations with elegans

“…Although much is known about the neurological basis of sickness behavior, our understanding of its molecular triggers is extremely limited. Recent work reported by Kim and colleagues (Meisel et al, 2014) may offer new insight.…”

“…Despite how common sickness behavior is, its molecular basis is not well understood. In a study published in Cell, Kim and colleagues (Meisel et al, 2014) implicate bacterial secondary metabolites as triggers of neural TGF-b signaling, which results in behavioral change during infection.…”

“…The work by Kim et al (Meisel et al, 2014) may have direct implications for human health. Humans broadly express TGF-b and its receptors in the central nervous system (CNS).…”

Animal–microbe interactions and the evolution of nervous systems

“…Under these conditions, the bacterial metabolites phenazine-1-carboxamide and pyochelin are detected by the ASJ neurons, which then produce neuromodulators that alter activity in adjacent neurons. This activity leads the animal to seek higher oxygen environments, away from potential pathogens [13]. Thus, it appears that C. elegans possesses distinct sensory-neural pathways for generating appropriate behavioural responses to specific cues from potential microbial pathogens.…”