Longitudinal Analysis of Disease-Site Activities Impairing Wound Healing in Epidermolysis Bullosa and Development of Therapeutic Strategies
Abstract
Epidermolysis bullosa patients develop poorly healing skin wounds that are frequently colonized with microbiota. To evaluate the dynamics of the microbiota colonizing early, established, and chronic EB wounds, we conducted high throughput sequencing to define multiple metrics of the microbiome, including diversity, stability, and relative abundance of potential pathogens and identified mirobiomic features associated with disease clinical outcomes. We found that progression of RDEB wounds to chronic state is associated with reduced abundance of specific taxa and overall reduced diversity of bacterial communities. Specifically, it is characterized by disappearance of Corynebacterium, Propionobacterium, and several other taxa and accumulation of pre-dominantly Staphylococcus and Pseudomonas species in chronic wounds. Because T cells play an important role in clearing such pathogens, we defined the status of adaptive T cell-mediated immunity in wounds. We found that RDEB wounds and epithelial cells are most frequently infected with Staphylococcus sp. and Pseudomonas sp. The wound-associated T cells contain populations of CD4+ and CD8+ peripheral memory T cells that respond to soluble microbial antigens by proliferating and secreting interferon gamma (IFNgamma). Also, CD8+ cytotoxic T lymphocytes recognize S. aureus-infected RDEB keratinocytes and respond by producing interleukin-2 (IL-2) and IFNgamma and degranulating and cytotoxically killing infected cells. Prolonged exposure of RDEB-derived T cells to microbial antigens in vitro does not trigger PD1-mediated T cell exhaustion but induces differentiation of the CD4high population into CD4highCD25+FoxP3+ regulatory T cells. Collectively, our data demonstrated that adaptive T cell-mediated immunity could clear infected cells from wound sites, but these effects might be inhibited by PD1/Treg-mediated immuno-suppression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2021
- Accession Number
- AD1155394
Entities
People
- Jouni Uitto
- Olga Igoucheva
- Vitali Y Alexeev
Organizations
- Thomas Jefferson University