The novel Listeria monocytogenes bile sensor BrtA controls expression of the cholic acid efflux pump MdrT

Mammalian bile has potent anti-microbial activity, yet bacterial pathogens of the gastrointestinal tract and hepatobiliary system nonetheless persist and replicate within bile-rich environments. Listeria monocytogenes, a Gram-positive pathogen, encounters bile at three stages throughout its infectious cycle in vivo: in the gut during initial infection, in the liver where it replicates robustly and in the gallbladder, from which it can return to the intestine and thence to the environment. The mechanisms by which L. monocytogenes senses mammalian bile and counteracts its bactericidal effects are not fully understood. In this report, we have determined the L. monocytogenes bile-induced transcriptome, finding that many critical virulence factors are regulated by bile. Among these, the multidrug efflux pumps MdrM and MdrT, previously shown to be critical for the bacterial provocation of a pathogenesis-promoting host innate immune response, are robustly and specifically induced by the bile component cholic acid. This induction is mediated by BrtA, the first identified L. monocytogenes sensor of bile, which loses the ability to bind to and repress the mdrT promoter in the presence of cholic acid. We show that MdrT can export cholic acid, and that ΔmdrT bacteria are significantly attenuated both in vitro when exposed to cholic acid or bile, and in vivo in the gallbladders and livers of infected mice.