Pathogen and host-derived lipid membranes governing Staphylococcus aureus-mediated skin inflammation

点击翻译按钮获取中文摘要

Human skin is colonized by a complex microbiome constantly releasing pro-inflammatory microbe-associated molecular pattern (MAMP) molecules. It has remained largely unclear how permanent skin inflammation is avoided while invading pathogens still lead to rapid pro-inflammatory responses. The keratinized, dead corneocytes forming the upper skin layers are embedded in a protective layer of lipid lamellar membranes, which may prevent bacterial molecules from reaching MAMP-responsive live keratinocytes. Atopic dermatitis (AD) patients exhibit major defects in skin barrier function, in particular in the integrity of lipid lamellar membranes. The bacterial pathogen Staphylococcus aureus is a frequent cause of skin inflammation in AD patients. It activates live keratinocytes by releasing bacterial lipoproteins, potent agonists of the Toll-like receptor (TLR) 2. We analysed in the first phase of the project how bioactive bacterial and host peptides contribute to activation and inflammation. We found that lipoproteins can only be efficiently released by S. aureus with the help of surfactant-like phenol-soluble modulin (PSM) peptides, which mobilize the hydrophobic lipoproteins in an unclear fashion. Preliminary data suggest that PSMs promote the release of membrane vesicles (MVs) containing the membrane-embedded lipoproteins from S. aureus. Based on these findings we propose that (i) S. aureus activates keratinocytes in AD largely by lipoprotein-containing MVs and that (ii) such MVs are retained by skin lamellar membranes in healthy skin while they can easily reach TLR2-expressing keratinocytes in AD patients with compromised skin lamellar membrane integrity to cause inflammation.We propose to investigate these hypotheses by elucidating how and when S. aureus releases MVs, if most bacterial lipoproteins are associated with MVs, and how they can leave MVs to activate TLR2 in keratinocytes. In vitro and in vivo experiments are envisaged to elucidate if and how lamellar membrane dysfunction impacts on TLR2-dependent skin inflammation and if supplementation of AD skin with lipid cocktails can help to prevent the access of S. aureus lipoproteins to MAMP-responsive keratinocytes. Our project will help to elucidate key processes of bacterial MAMP releases and of skin barrier function and it should inspire better clinical interventions against skin inflammation in AD patients and other chronic inflammatory skin diseases.