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Expression and regulation of phenol-soluble modulins and enterotoxins in foodborne Staphylococcus aureus.

ABSTRACT: Although high levels of staphylococcal phenol-soluble modulins (PSMs) in clinical methicillin-resistant Staphylococcus aureus (MRSA) has been shown to correlate with bacterial virulence, the PSMs expression in foodborne Staphylococcus aureus (S. aureus), as well as its association with staphylococcal food poisoning (SFP) was not yet clear. We collected a panel of 350 foodborne and 127 clinic-derived S. aureus strains and compared their PSMs expression. Overall, foodborne strains exhibited higher PSMs than clinical isolates, indicating a potential pathological significance of PSMs in staphylococcal food contamination. Furthermore, PSMs expression and staphylococcal enterotoxins (SEs) levels in relation to antibiotic sensitive and resistant strains were analysed. While the co-expression of PSMs and SEs was confirmed, one typical foodborne strain simultaneously yielding PSMs, SEB and SED was selected. By comparing this wildtype strain to a series of gene-deficient mutants, we concluded that PSMs and SEs expressions both relied on staphylococcal accessory regulator A initiation in the early stage of accessory gene regulator control, yet their succedent regulations differentiated to RNAIII-dependent and independent, respectively. These data provided preliminary insight into PSMs and SEs expression in foodborne S. aureus, and may guide the further studies on PSMs effects in SFP.

SUBMITTER: Wu X

PROVIDER: S-EPMC6250609 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Incomplete killing of bacterial pathogens by antibiotics is an underlying cause of treatment failure and accompanying complications. Among those avoiding chemotherapy are persisters being individual cells in a population that for extended periods of time survive high antibiotic concentrations proposedly by being in a quiescent state refractory to antibiotic killing. While investigating the human pathogen Staphylococcus aureus and the influence of growth phase on persister formation, we noted that spent supernatants of stationary phase cultures of S. aureus or S. epidermidis, but not of distantly related bacteria, significantly reduced the persister cell frequency upon ciprofloxacin challenge when added to exponentially growing and stationary phase S. aureus cells. Curiously, the persister reducing activity of S. aureus supernatants was also effective against persisters formed by either S. carnosus or Listeria monocytogenes. The persister reducing component, which resisted heat but not proteases and was produced in the late growth phase in an agr quorum-sensing dependent manner, was identified to be the phenol-soluble modulin (PSM) toxins. S. aureus express several PSMs, each with distinct cytolytic and antimicrobial properties; however, the persister reducing activity was specifically linked to synthesis of the PSM? family. Correspondingly, a high-persister phenotype of a PSM? mutant was observed upon fluoroquinolone or aminoglycoside challenge, demonstrating that the persister reducing activity of PSMs can be endogenously synthesized or extrinsically added. Given that PSMs have been associated with lytic activity against bacterial membranes we propose that PSM toxins increase the susceptibility of persister cells to killing by intracellularly acting antibiotics and that chronic and re-occurring infections with quorum sensing, agr negative mutants may be difficult to treat with antibiotics because of persister cells formed in the absence of PSM toxins.

Project description:Small RNAs (sRNAs) remain an understudied class of regulatory molecules in bacteria in general and in Gram-positive bacteria in particular. In the major human pathogen Staphylococcus aureus, hundreds of sRNAs have been identified; however, only a few have been characterized in detail. In this study, we investigate the role of the sRNA Teg41 in S. aureus virulence. We demonstrate that Teg41, an sRNA divergently transcribed from the locus that encodes the cytolytic alpha phenol-soluble modulin (αPSM) peptides, plays a critical role in αPSM production. Overproduction of Teg41 leads to an increase in αPSM levels and a corresponding increase in hemolytic activity from S. aureus cells and cell-free culture supernatants. To identify regions of Teg41 important for its function, we performed an in silico RNA-RNA interaction analysis which predicted an interaction between the 3' end of Teg41 and the αPSM transcript. Deleting a 24-nucleotide region from the S. aureus genome, corresponding to the 3' end of Teg41, led to a 10-fold reduction in αPSM-dependent hemolytic activity and attenuation of virulence in a murine abscess model of infection. Restoration of hemolytic activity in the Teg41Δ3' strain was possible by expressing full-length Teg41 in trans Restoration of hemolytic activity was also possible by expressing the 3' end of Teg41, suggesting that this region of Teg41 is necessary and sufficient for αPSM-dependent hemolysis. Our results show that Teg41 is positively influencing αPSM production, demonstrating for the first time regulation of the αPSM peptides by an sRNA in S. aureusIMPORTANCE The alpha phenol-soluble modulins (αPSMs) are among the most potent toxins produced by Staphylococcus aureus Their biological role during infection has been studied in detail; however, the way they are produced by the bacterial cell is not well understood. In this work, we identify a small RNA molecule called Teg41 that plays an important role in αPSM production by S. aureus Teg41 positively influences αPSM production. The importance of Teg41 is highlighted by the fact that a strain containing a deletion in the 3' end of Teg41 produces significantly less αPSMs and is attenuated for virulence in a mouse abscess model of infection. As the search for new therapeutic strategies to combat S. aureus infection proceeds, Teg41 may represent a novel target.

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Expression and regulation of phenol-soluble modulins and enterotoxins in foodborne Staphylococcus aureus.

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