Immunoprophylaxis and Immunotherapy of Staphylococcus Epidermidis Infections

Challenges and Prospects

Lieve Van Mellaert; Mohammad Shahrooei; Dorien Hofmans; Johan Van Eldere

Disclosures

Expert Rev Vaccines. 2012;11(3):319-334. 

In This Article

Other Potential Virulence Factors

S. epidermidis also produces other compounds with a possible role in invading host tissues or interfering with host immune responses, thereby enabling bacterial growth and survival in the host. These compounds include protective exopolymers, pathogen-associated molecular patterns (PAMPs) recognized by the host innate immune system, molecules sensing antimicrobial peptides (AMPs) and secretory products such as toxins, enzymes and bacteriocins.

Protective Exopolymers

As a major structural compound of the adhesive extracellular polymeric substance layer, PIA also protects S. epidermidis cells against phagocytosis by human polymorphonuclear leukocytes (PMNs) and killing by human antibacterial peptides. An increased sensitivity to PMN phagocytosis and to the skin-associated AMPs such as LL37, β-defensin 3 and dermcidin was observed in an ica-negative S. epidermidis strain. A comparable susceptibility was obtained in an icaB mutant, indicating that immune evasion by PIA is largely based on its de-acetylation. Thus, the cationic nature of the de-acetylated PIA serves as a mechanical barrier blocking antibacterial peptides and inhibiting PMN attack.[28,45] The protective effect of PIA against cationic antibacterial peptides is probably based on electrostatic repulsion, but even the anionic peptide dermcidin can be trapped and disarmed within the cationic PIA network.[45] In addition, it was reported that PMNs were rather immobile in S. epidermidis biofilms and could only phagocytize the bacterial cells in their immediate neighborhood.[46]

Nevertheless, because not all S. epidermidis strains are equipped with the PIA-encoding ica operon, other protective mechanisms against human immune responses were sought.

Recently, it has been reported that Aap- and Embp-mediated biofilm formation protected S. epidermidis cells from uptake by mouse macrophage-like cells as in PIA-dependent biofilms. In addition, compared with biofilm-negative strains, the PIA-dependent and the PIA-independent S. epidermidis biofilm types reduced the inflammatory macrophage response, resulting in diminished NF-κB activation and less IL-1β production. These results provide more insight into the mechanisms that might explain the chronic and persistent character of S. epidermidis biomaterial-related infections.[47]

Next, genomic analysis of the ica-negative S. epidermidis ATCC12228 revealed the presence of a cap locus showing high similarity to the virulence-encoding cap locus of Bacillus anthracis. This cap locus, absent in S. aureus but ubiquitous among clinical and commensal S. epidermidis isolates, codes for the production of anionic poly-γ-DL-glutamic acid (PGA). This surface-attached polymer not only contributes to resistance to high salt concentrations, but also protects against innate host defense by means of resistance to AMPs and neutrophil phagocytosis. PGA, which remarkably does not influence aggregation behavior or biofilm formation of S. epidermidis in vitro, was shown to be a key factor for successful skin colonization and survival during biomaterial-related infections.[48]

Pathogen-associated Molecular Patterns

As part of the innate immune system, structures at the bacterial surface, the so-called modulins or PAMPs, are recognized as nonself by pathogen recognition receptors such as Toll-like receptors. Similar to other Gram-positive bacteria, several structures at the S. epidermidis surface function as a PAMP, which include lipoteichoic acids, lipoproteins and peptidoglycan. Recently, PSMs have also been designated as PAMPs because the PSM complex exerts strong and diverse proinflammatory activities, such as chemotactic attraction of PMNs and monocytes, stimulation of cytokine production and subsequent release of cytokines by macrophages. Consequently, PSM production may contribute to abscess formation and leakage of toxic enzymes and oxygen metabolites by neutrophils, with damage to surrounding tissues. This leads not only to the release of nutrients for the established biofilm, but also to possible development of an S. epidermidis-caused septic shock.[49,50]

Notwithstanding the fact that PIA is clearly involved in S. epidermidis immune evasion, it has recently also been identified as a PAMP because it was shown that PIA induces IL-8 expression in human astrocytes.[51] This possible dual role of PIA, acting as a trigger of the innate immune response and as an inhibitor of the same system, reveals the complexity of S. epidermidis biofilm formation and infections and of the relationship between this opportunistic pathogen and its host.

Remarkably, the mentioned autolysin AtlE has recently been described to be additionally involved in internalization of S. epidermidis in endothelial cells via binding to a surface protein, which may provide a novel mechanism for this nosocomial pathogen to evade the host immune system and antibiotic treatment. As such, AtlE may be a key factor in the etiology of chronic and relapsing S. epidermidis infections.[52]

Capacity to Sense AMPs

To colonize or invade the human body, S. epidermidis needs to be protected against AMPs, one of the defense mechanisms of the innate immune system. Using a whole-genome transcriptomic approach, S. epidermidis genes activated in the presence of a subinhibitory concentration of human β-defensin-3 were identified. Further analysis of the genome sequence next to the activated genes revealed a unique AMP-sensing (aps) system. Activation of this system by β-defensin-3 results in D-alanylation of TAs and lysylation of phospholipids. Both reactions render the bacterial surface less anionic, reducing cationic AMP attraction. Sensing of cationic AMP additionally activated two genes with homology to S. aureus, vraF and vraG, which are supposed to function as AMP exporters.[53]

Production of Toxins, Extracellular Enzymes & Bacteriocins

S. epidermidis toxins are mainly limited to δ-toxin – identical to PSMγ – and PSMδ, although other toxins might be strain-specifically produced. Similar to host-derived AMPs, PSMγ and PSMδ form multimeric complexes exhibiting a strong α-helical structure that enables disruption of lipid membranes. The cytolytic capacity of S. epidermidis PSMδ on leukocytes was shown to be high compared with PSMγ, but its expression level was low.[54] These PSMs might cause tissue damage on crossing the skin barrier, but their function as an antimicrobial agent acting in concert with epithelial AMPs is above all important for the commensal lifestyle of S. epidermidis. The cooperation of PSMs with host-derived AMPs can benefit cutaneous immune defense by selectively inhibiting skin pathogens such as S. aureus and group A streptococci, without disturbing the normal skin microbiome.[55,56]

A set of extracellular enzymes with a putative role in tissue damaging and disintegration of the extracellular matrix, and therefore regarded as virulence factors, have also been described. To this group of enzymes belong an extracellular metalloprotease and a cysteine protease, both with elastase activity, and a few lipases important for skin colonization. In addition, S. epidermidis produces an extracellular serine protease involved in the processing of a self-produced bacteriocin (infra), a fatty acid-modifying enzyme, which destroys the bactericidal capacity of cholesterol, and protease SepA able to degrade AMPs.[54,57,58] Moreover, the serine protease Esp secreted by a subset of S. epidermidis strains hinders biofilm formation and nasal colonization of S. aureus.[1]

To compete with other commensal bacteria in successfully colonizing the skin, S. epidermidis produces bacteriocins, in particular lantibiotics, a group of AMPs directed against other Gram-positive bacteria. Lantibiotics isolated from S. epidermidis, so far, include the well-characterized epidermin, epicidin, pep5, epilancin K7 and 15X.[59]

Taken together, although S. epidermidis does not produce many toxins, it turns out to be an excellently armed microorganism to colonize the human skin as a commensal and to survive in the body as an opportunistic pathogen.

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