Important work from our long-time SALSAmigos at University of Miami suggests that the nearly ubiquitous S. aureus might be, in some instances, a more sinister player in promoting a potentially deleterious pro-inflammatory and anti-regenerative state by upregulating microRNA 15B-5P.
Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes in which bacterial presence, including its frequent colonizer Staphylococcus aureus, contribute to inhibition of healing. MicroRNAs (miRs) play a role in healing and host response to bacterial pathogens. However, the mechanisms by which miR response to cutaneous S. aureus contributes to DFU pathophysiology are unknown. Herein we show S. aureus inhibits wound closure and induces miR-15b-5p in acute human and porcine wound models, and in chronic DFUs. Transcriptome analyses of DFU tissue revealed induction of miR-15b-5p to be critical, regulating many cellular processes, including DNA repair and inflammatory response, by suppressing downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2 and KIT. Using a human wound model we confirmed that S. aureus-triggered miR-15b-5p induction results in suppression of inflammatory- and DNA repair-related genes, IKBKB and WEE1. Inhibition of DNA repair and accumulation of DNA breaks was functionally confirmed by the presence of the pH2AX within colonized DFUs. We conclude that S. aureus induces miR-15b-5p, subsequently repressing DNA repair and inflammatory response, revealing a previously unreported mechanism of inhibition of healing in DFUs. This underscores a previously unknown role of DNA damage repair in pathophysiology of DFU colonized with S. aureus.