Identification of a Peptide-Pheromone that Enhances <i>Listeria monocytogenes</i> Escape from Host Cell Vacuoles

<div><p><i>Listeria monocytogenes</i> is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following <i>L</i>. <i>monocytogenes</i> entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for <i>L</i>. <i>monocytogenes</i> secretion of a small peptide pheromone, pPplA, which enhances the escape of <i>L</i>. <i>monocytogenes</i> from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to <i>L</i>. <i>monocytogenes</i> its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol.</p>