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Staphylococcus aureus quorum sensing and the battle for control of epidermal proteases by the skin microbiome


The top layer of the skin provides our first line of innate defense against external stimuli and is regulated in part by serine protease activity. One stimulus is that of bacteria that cover the entirety of our skin surface and can directly interact with skin immune cells, including epidermal keratinocytes. During a disease state such as atopic dermatitis (AD), the composition of the skin bacteria, or skin microbiome, changes and there is increased colonization by the pathogenic Staphylococcus aureus (S. aureus). In this dissertation, we hypothesized that S. aureus could alter the protease activity of the epidermal skin barrier. We found that S. aureus could increase serine protease activity in both human keratinocytes and the murine epidermis in a strain and species dependent manner. Specifically a group of serine proteases known as the kallikreins (KLKs) showed increased expression and these are directly responsible for part of the increased serine protease activity and epidermal barrier damage caused by S. aureus.

Based upon the initial hypothesis, we further explored the mechanism of S. aureus induced serine protease activity in keratinocytes. We discovered that S. aureus phenol-soluble modulins (PSMs), specifically PSMα, are responsible for inducing serine protease activity in keratinocytes. Furthermore, PSMα as well as S. aureus secreted proteases are both necessary for inflammation and barrier damage on murine skin. Both of which are controlled via the S. aureus accessory gene regulator (agr) quorum sensing system.

This led us to further explore how to prevent S. aureus mediated epidermal barrier damage through targeting the agr system. We showed that coagulase-negative Staphylococci (CoNS) clinical isolates from AD patients could turn off the S. aureus agr system through use of their own agr systems and secretion of autoinducing peptides (AIPs). This prevented S. aureus induced barrier damage and inflammation in both human keratinocyte and mouse models. Overall, the data presented in this dissertation provides a novel mechanism for how S. aureus can drive AD–like skin inflammation and epidermal barrier damage through multiple mechanisms including the induction of endogenous serine protease activity. Secondly, targeting the agr quorum sensing system of S. aureus and virulence factor release by using our own healthy microbes can ultimately provide a novel therapeutic option to prevent skin inflammation and barrier damage.

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