Control of Bacterial Virulence through the Peptide Signature of the Habitat

摘要

To optimize fitness, pathogens selectively activatetheir virulence program upon host entry. Here, wereport that the facultative intracellular bacterium Listeriamonocytogenes exploits exogenous oligopeptides,a ubiquitous organic N source, to sense theenvironment and control the activity of its virulencetranscriptional activator, PrfA. Using a genetic screenin adsorbent-treated (PrfA-inducing) medium, wefound that PrfA is functionally regulated by the balancebetween activating and inhibitory nutritionalpeptides scavenged via the Opp transport system.Activating peptides provide essential cysteine precursorfor the PrfA-inducing cofactor glutathione (GSH).Non-cysteine-containing peptides cause promiscuousPrfA inhibition. Biophysical and co-crystallizationstudies reveal that peptides inhibit PrfA through stericblockade of the GSH binding site, a regulation mechanismdirectly linking bacterial virulence and metabolism.L. monocytogenes mutant analysis in macrophagesand our functional data support a model inwhich changes in the balance of antagonistic Oppimportedoligopeptides promote PrfA induction intracellularlyand PrfA repression outside the host.