Uncovering Novel Microbial Factors That Enhance Wound Repair

Skin injuries and repair failures are a significant public health concern, with over 100 million new acute skin wounds occurring annually and non-healing wounds affecting 2% of the U.S. population. The economic burden of wound management is substantial, with annual treatment costs exceeding $25 billion. Despite this impact, effective interventions to improve skin healing outcomes remain elusive. Skin injuries expose internal organs to environmental threats and allow the translocation of surface microbes. While the pathological role of microbes in non- healing wounds is well studied, their contribution to acute healing and the potential of specific microbial factors to serve as pro-repair signals remain unclear. We and others have shown that signals from the skin microbiome can modulate cutaneous immunity and barrier function, suggesting that microbially-derived signals may also enhance repair. Our strong preliminary data show that several Staphylococcal species are enriched in acute human wounds. Using an in vivo screen with a newly developed physiological microbial translocation wound model, we identified specific Staphylococcal species that enhance repair four-fold without causing infection. Loss-of-function bacterial genetics revealed that enhanced Staphylococcal-driven healing depends upon toxin production. We hypothesize that Staphylococcal toxins act as novel pathogen-associated molecular patterns for repair by modulating both epidermal and dermal repair processes. Aim 1 will identify the specific toxins and epithelial responses involved in promoting repair, while Aim 2 will investigate how microbial toxins drive dermal repair responses. This research will leverage cutting-edge spatial omics technologies, including spatial transcriptomics and spatial lipidomics, combined with rigorous bacterial genetics and in vivo functional studies in repair. Our efforts promise to uncover non- canonical microbial mechanisms that enhance skin repair, potentially leading to innovative microbe-based therapies to boost this fundamental process and increase barrier fitness.