Arginine sensing regulates virulence gene expression and disease progression in enteric pathogens.

Microbiota, host and dietary metabolites/signals compose the rich gut chemical environment,which profoundly impacts virulence of enteric pathogens. Enterohemorrhagic Escherichia coli(EHEC) engages a syringe-like machinery named a type three secretion system (T3SS) to injecteffectors within host cells that lead to intestinal colonization and disease. We previouslyconducted a high throughput screen to identify metabolic pathways that affect T3SS expression.Here we show that in the presence of arginine, the arginine sensor ArgR, identified through thisscreen, directly activates expression of the genes encoding the T3SS. Exogenously addedarginine induces EHEC virulence gene expression in vitro. Congruently, a mutant deficient inarginine transport (?artP) had decreased virulence gene expression. ArgR also augments murinedisease caused by Citrobacter rodentium, which is a murine pathogen extensively employed as asurrogate animal model for EHEC. The source of arginine sensed by C. rodentium is not dietary.At the peak of infection, C. rodentium increases the arginine concentration in the colon throughdownregulation of the host SLC7A2 transporter. This increase in the concentration of colonicarginine promotes virulence gene expression in C. rodentium. Arginine is an importantmodulator of the host immune response to pathogens. Here we add that arginine also directlyimpacts bacterial virulence. These findings suggest that a delicate balance between host andpathogen responses to arginine occur during disease progression.