Listeriolysin S, a Novel Peptide Haemolysin Associated with a Subset of Lineage I Listeria monocytogenes

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Abstract
Streptolysin S (SLS) is a bacteriocin-like haemolytic and cytotoxic virulence factor that plays a key role in the virulence of Group A Streptococcus (GAS), the causative agent of pharyngitis, impetigo, necrotizing fasciitis and streptococcal toxic shock syndrome. Although it has long been thought that SLS and related peptides are produced by GAS and related streptococci only, there is evidence to suggest that a number of the most notorious Gram-positive pathogenic bacteria, including Listeria monocytogenes, Clostridium botulinum and Staphylococcus aureus, produce related peptides. The distribution of the L. monocytogenes cluster is particularly noteworthy in that it is found exclusively among a subset of lineage I strains; i.e., those responsible for the majority of outbreaks of listeriosis. Expression of these genes results in the production of a haemolytic and cytotoxic factor, designated Listeriolysin S, which contributes to virulence of the pathogen as assessed by murine- and human polymorphonuclear neutrophil–based studies. Thus, in the process of establishing the existence of an extended family of SLS-like modified virulence peptides (MVPs), the genetic basis for the enhanced virulence of a proportion of lineage I L. monocytogenes may have been revealed. Listeria monocytogenes is known to produce only one haemolytic factor that plays an important role in its pathogenic cycle—that is, the cholesterol-dependent Listeriolysin O. However, here we identify a second haemolysin, which is present in a subset of strains of lineage I, the evolutionary lineage of L. monocytogenes that contributes to the majority of spontaneous and epidemic outbreaks of listeriosis. This second haemolysin is only induced under oxidative stress conditions and contributes to murine virulence and in survival in polymorphonuclear neutrophils. Bioinformatic analysis suggests that the haemolysin Listeriolysin S (LLS) is post-translationally modified and belongs to a family of modified virulence peptides, including the potent virulence factor Streptolysin S (SLS), a peptide cytolysin produced by Streptococcus pyogenes, and several as-yet uncharacterised members of the same family in other pathogens. Therefore, en route to establishing that some L. monocytogenes produce more than one haemolysin, we have uncovered a virulence factor that is exclusively associated with a subset of the lineage I evolutionary line and that is also the first non-streptococcal representative of a potentially extended family of SLS-like peptides.