Resistance to Bile

The ability to colonize the gall bladder was recently shown to be an important feature of virulent L. monocytogenes [90]. The bacteria have hence to cope with the cytotoxic effects of bile when residing in the gall bladder but also in the small intestine. The comparison of the L. monocytogenes EGD-e and L. innocua genomes [2] has revealed the presence of a L. monocytogenes-specific gene, termed bsh (lmo2067), encoding a bile salt hydrolase (BSH) [91]. Bile salts are the end products of the cholesterol metabolism in the liver and are stored in the gall bladder and released into the duodenum, helping fat digestion. In addition, bile salts are known to have antimicrobial activity since they are amphipathic molecules which can attack and degrade lipid membranes. Some intestinal microorganisms have hence evolved mechanisms to resist the detergent action of bile, including the synthesis of porins, efflux pumps and transport proteins [2]. Others produce bile salt hydrolases which transform and inactivate the bile salts. The deletion of the bsh gene from the L. monocytogenes chromosome results in an increase in bile sensitivity, reduced virulence, and reduced liver colonization after infection of mice, demonstrating that BSH is a novel L. monocytogenes virulence factor involved in the intestinal and hepatic phases of listeriosis. In addition, the bsh gene has been reported to be positively regulated by the central listerial virulence regulator PrfA in vivo [91], but PrfA-dependent transcription ofbsh could not be demonstrated in vitro [57]. Analysis of L. monocytogenes deletion mutants in two other bile-associated loci (pva or lmo0446 and btlB or lmo0754) revealed a role at least of the btlB gene product in resisting the acute toxicity of bile and bile salts, particularly glyco-conjugated bile salts at low pH, but without actual BSH activity [92]. Finally, in silico analysis of the L. monocytogenes EGD-e genome revealed a putative bile exclusion system encoded by the bilEA and bilEB genes (lmo1421 and lmo1422) [93].

The bilE system mediates resistance to bile through the active export of bile from the bacterial cell, especially under conditions which mimic the situation of the upper intestinal tract. Furthermore, a L. monocytogenes DbilE mutant shows much higher levels of intracellular bile than the wild-type strain and the mutant is severely impaired in virulence upon oral administration.

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