Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy
When an organism encounters a pathogen, the host innate immune system is activated to defend against pathogen colonization and the toxic xenobiotics produced.  C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa (PA14) including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy to PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave while continuing to feed on the pathogen even when a non-pathogenic food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display a typical intestinal distension from PA14 colonization and eventual demise, but surprisingly, fail to learn to avoid pathogen with training.  SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling from both neurons and non-neuronal tissues that drives the pathogen apathy behavior and pleiotropic responses to selective serotonin reuptake inhibitors (SSRIs). Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival. Overall design: To investigate the effect of exposure to Pseudomonas aeruginosa (PA14) in wildtype and skn-1gf(lax188) C elegans. E. coli OP50 was used as the control exposure. Worms were raised on OP50 and then either moved to a plate with OP50 or PA14 for 4 hours before collection at L4 stage.