Staphylococcus epidermidis Strategies to Avoid Killing by Human Neutrophils

Abstract

Staphylococcus epidermidis is a leading nosocomial pathogen. In contrast to its more aggressive relative S. aureus, it causes chronic rather than acute infections. In highly virulent S. aureus, phenol-soluble modulins (PSMs) contribute significantly to immune evasion and aggressive virulence by their strong ability to lyse human neutrophils. Members of the PSM family are also produced by S. epidermidis, but their role in immune evasion is not known. Notably, strong cytolytic capacity of S. epidermidis PSMs would be at odds with the notion that S. epidermidis is a less aggressive pathogen than S. aureus, prompting us to examine the biological activities of S. epidermidis PSMs. Surprisingly, we found that S. epidermidis has the capacity to produce PSMδ, a potent leukocyte toxin, representing the first potent cytolysin to be identified in that pathogen. However, production of strongly cytolytic PSMs was low in S. epidermidis, explaining its low cytolytic potency. Interestingly, the different approaches of S. epidermidis and S. aureus to causing human disease are thus reflected by the adaptation of biological activities within one family of virulence determinants, the PSMs. Nevertheless, S. epidermidis has the capacity to evade neutrophil killing, a phenomenon we found is partly mediated by resistance mechanisms to antimicrobial peptides (AMPs), including the protease SepA, which degrades AMPs, and the AMP sensor/resistance regulator, Aps (GraRS). These findings establish a significant function of SepA and Aps in S. epidermidis immune evasion and explain in part why S. epidermidis may evade elimination by innate host defense despite the lack of cytolytic toxin expression. Our study shows that the strategy of S. epidermidis to evade elimination by human neutrophils is characterized by a passive defense approach and provides molecular evidence to support the notion that S. epidermidis is a less aggressive pathogen than S. aureus.

Coagulase-Negative Staphylococci

“…Thus, S. epidermidis has the potential to produce an effective cytotoxin; however, the production of strongly cytolytic PSMs is low, explaining why culture supernatants of S. epidermidis have little or no capacity to lyse PMNs (331). These data indicate that the strategy of S. epidermidis to evade the human immune system depends on passive defense mechanisms mediated by enzymatic activities, such as the protease SepA that cleaves AMPs, rather than on being an aggressive pathogen that produces a variety of potent cytotoxins, as in the case of S. aureus (331).…”

How Staphylococcus aureus biofilms develop their characteristic structure

“…PSMs are staphylococcal peptides with an α-helical, amphipathic structure, which gives them surfactant-like characteristics (13)(14)(15). They are genome-encoded and found in most staphylococcal strains, with a given species producing PSMs of usually only minor amino acid sequence similarity to PSMs of other species (16).…”

Staphylococcus aureus toxins – Their functions and genetics

“…Secondly, PSMs have 26 proinflammatory properties, and they induce chemotaxis and activation of human 27 neutrophils, as well as cytokine expression (Wang, Braughton et al 2007;Queck, Khan et 28 al. 2009;Cheung, Rigby et al 2010). This response is mediated by activation of the 29 human formyl peptide receptor 2 (FPR2) (Kretschmer, Gleske et al 2010).…”