title: Constitutive activation of PrfA tilts the balance of Listeria monocytogenes fitness towards life within the host versus environmental survival.
abstract: PrfA is a key regulator of Listeria monocytogenes pathogenesis and induces the expression of multiple virulence factors within the infected host. PrfA is post-translationally regulated such that the protein becomes activated upon bacterial entry into the cell cytosol. The signal that triggers PrfA activation remains unknown, however mutations have been identified (prfA* mutations) that lock the protein into a high activity state. In this report we examine the consequences of constitutive PrfA activation on L. monocytogenes fitness both in vitro and in vivo. Whereas prfA* mutants were hyper-virulent during animal infection, the mutants were compromised for fitness in broth culture and under conditions of stress. Broth culture prfA*-associated fitness defects were alleviated when glycerol was provided as the principal carbon source; under these conditions prfA* mutants exhibited a competitive advantage over wild type strains. Glycerol and other three carbon sugars have been reported to serve as primary carbon sources for L. monocytogenes during cytosolic growth, thus prfA* mutants are metabolically-primed for replication within eukaryotic cells. These results indicate the critical need for environment-appropriate regulation of PrfA activity to enable L. monocytogenes to optimize bacterial fitness inside and outside of host cells.
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Bruno
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Freitag
mesh_terms: D000483:Alleles; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001435:Bacteriophages / Q000378:metabolism; D002244:Carbon / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000737:chemistry; D008089:Listeria monocytogenes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012808:Sigma Factor / Q000378:metabolism; D013234:Stem Cells
chemical_list: D001426:Bacterial Proteins; D010454:Peptide Termination Factors; C545356:PrfA protein, Listeria monocytogenes; C480945:SigB protein, Listeria monocytogenes; D012808:Sigma Factor; D002244:Carbon; D005947:Glucose; D005990:Glycerol