Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis

Abstract

Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides’ capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus–mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.

Oxidative stress drives the selection of quorum sensing mutants in the Staphylococcus aureus population

“…S1). Other mechanisms to inactivate Agr during infection, e.g., through hemoglobin (53), lipoproteins (54), oxidants (55), or microbial interference (28,56,57) may similarly function to maintain producer-cheater homeostasis.…”

“…This indicates that, on the population level, several mechanisms may have evolved to maintain the balance. The Agr system was found to be inactive during nose colonization (60), possibly due to Agr interference imposed by other staphylococci (57) in the skin microbiome. Many of the globally spreading haMRSA strains are characterized by low Agr activity (30) which could also be seen as a strategy to avoid agr mutant selection.…”

Neutrophil Recruitment to Noninvasive MRSA at the Stratum Corneum of Human Skin Mediates Transient Colonization

“…The PMN mediated reduction of bacterial numbers at the skin surface suggests that this response could also influence the ability of Staphylococci to trigger quorum sensing and its associated virulence. In the search for alternative treatments for MRSA, quorum sensing has generated much interest, with blockage or interference being shown to be effective in reducing pathogenesis during skin infection (Paharik et al, 2017;Parlet et al, 2019;Williams et al, 2019). Our model may be very useful in expanding this work by adding the human tissue microenvironment to these types of studies.…”

The manifold roles of microbial ribosomal peptide–based natural products in physiology and ecology

“…Thus, it can be envisioned that AIP-mediated interspecies cross-talks play a role in maintaining homeostasis of related microbiota in a complex environment. Indeed, as mentioned above, it has been evidenced that commensal, non-S. aureus staphylococcal strains in the human skin microbiota can block the agr QS system of S. aureus by secreting different AIPs, hence preventing its damage to the skin (137,154). Such a phenomenon has implications for the development of therapeutic strategies using AIP variants (153,155,156).…”