PhoP-PhoQ-Regulated Loci Are Required for Enhanced Bile Resistance in Salmonella spp.

As enteric pathogens, Salmonella spp. are resistant to the actions of bile. Salmonella typhimurium and Salmo-nella typhi strains were examined to better define the bile resistance phenotype. The MICs of bile for wild-type S. typhimurium and S. typhi were 18 and 12%, respectively, and pretreatment of log-phase S. typhimurium with 15 % bile dramatically increased bile resistance. Mutant strains of S. typhimurium and S. typhi lacking the vir-ulence regulator PhoP-PhoQ were killed at significantly lower bile concentrations than wild-type strains, while strains with constitutively active PhoP were able to survive prolonged incubation with bile at concentrations of>60%. PhoP-PhoQ was shown to mediate resistance specifically to the bile components deoxycholate and con-jugated forms of chenodeoxycholate, and the protective effect was not generalized to other membrane-active agents. Growth of both S. typhimurium and S. typhi in bile and in deoxycholate resulted in the induction or re-pression of a number of proteins, many of which appeared identical to PhoP-PhoQ-activated or-repressed products. The PhoP-PhoQ regulon was not induced by bile, nor did any of the 21 PhoP-activated or-repressed genes tested play a role in bile resistance. However, of the PhoP-activated or-repressed genes tested, two (prgC and prgH) were transcriptionally repressed by bile in the medium independent of PhoP-PhoQ. These data suggest that salmonellae can sense and respond to bile to increase resistance and that this response likely includes proteins that are members of the PhoP regulon. These bile- and PhoP-PhoQ-regulated products may play an important role in the survival of Salmonella spp. in the intestine or gallbladder