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Host response of human epidermis to Methicillin-resistant Staphylococcus aureus biofilm infection and synthetic antibiofilm peptide treatment

ABSTRACT: Bacterial biofilm infections associated with wounded skin are prevalent, recalcitrant and in urgent need of treatments. Additionally, host responses in the skin to biofilm infections are not well understood. Here we employed a human organoid skin model to explore the transcriptomic changes of thermally-injured epidermis to Methicillin-resistant Staphylococcus aureus (MRSA) biofilm colonization. MRSA biofilm impaired skin barrier function, enhanced extracellular matrix remodelling, elicited inflammatory responses including IL-17, IL-12 family and IL-6 family interleukin signalling and modulated skin metabolism. Synthetic antibiofilm peptide DJK-5 effectively diminished MRSA biofilm associated with wounded human ex vivo skin. In the epidermis, DJK-5 shifted the overall skin transcriptome towards homeostasis including modulating the biofilm induced inflammatory response, promoting the skin DNA repair function, and downregulating MRSA invasion of thermally damaged skin. These data revealed the intrinsic promise of synthetic peptides in treating inflammation and biofilm infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210640 | GEO | 2022/11/04

REPOSITORIES: GEO

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Project description:Dendritic epidermal T cells (DETC) reside in murine skin and participate in homeostasis and wound repair. Upon wounding, DETC become activated through the recognition of an unidentified ligand expressed by keratinocytes proximal to sites of injury. Such DETC activation is mediated through a monoclonal T cell receptor (TCR). Using a soluble form of this monoclonal TCR, we have shown that keratinocytes upregulate DETC TCR ligands in wounded tissue within 2 hours following wounding. Down-modulation of the ligand is seen 3 hours following wounding, and no expression is evident in non-wounded skin. In vitro studies on cell lines which express this unknown ligand indicate that antigen recognition by the DETC TCR is dependent upon N-linked glycosylation of the ligand. Given the glycosylation sensitivity of the ligand and the restricted expression following wounding, we are interested in pursuing microarray analysis to identify genes that are modulated in keratinocytes in response to wounding. Keratinocytes represent 90% of the cells in the epidermis (DETC and Langerhan’s cells make up the remaining 10%). As such, we propose to isolate RNA from whole epidermis under either wounded or resting conditions. In addition to comparing RNA from wounded and non-wounded epidermis, we would like to compare RNA from tissue that has been wounded for different times. Initially, we would like to analyze 4 sampes (non-wounded epidermis, and epidermal cells isolated 30 minutes, 2 hours, and 4 hours following wounding). These time points would correlate to a period prior to cell surface expression of ligand (30 minutes), during cell surface expression (2 hours), and following down regulation of cell surface expression (4 hours). In addition to providing possible identification of the unknown DETC TCR ligand, such analysis would provide novel information about early responses by keratinocytes in response to physical wounding in vivo. We propose to isolate RNA from whole epidermis under either wounded or resting conditions. In addition to comparing RNA from wounded and non-wounded epidermis, we would like to compare RNA from tissues that has been wounded for different times.

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Host response of human epidermis to Methicillin-resistant Staphylococcus aureus biofilm infection and synthetic antibiofilm peptide treatment

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