225 Induction of protective antimicrobial responses mediated by NOD2 as a treatment for wounds infected with multidrug-resistant bacteria

Of critical concern is the increasing antimicrobial resistance of bacteria and decreasing availability effective treatments for these multi-drug resistant (MDR) strains. The activity pattern recognition receptor NOD2 increased by pyrimidine synthesis inhibitor N-phosphonacetyl-l-aspartate (PALA) in vitro. We investigated efficacy a topical PALA formulation to enhance NOD2-mediated protective immune responses as novel therapeutic approach wounds infected with MDR bacteria. In mouse model MRSA biopsy wounds, application bacterial clearance from wound tissue early day 4 post-infection without impairing healing kinetics. enhanced corresponded epidermal dermal production peptides (AMPs), including Reg3β, Reg3γ, mBD14 mBD3, well levels TNF-α, IL-1β, IL-17A, IL-22, indicating an involvement IL-17/IL-22 axis this response. expression was required response, Nod2-/- mice exhibited loss PALA-enhanced clearance, AMP expression, Th17 cytokine expression. Molecular analyses vitro demonstrate that treatment activation transcription factor IRF1 upregulation IL-17C, protein kinase RIP2, but not adaptor MAVS, demonstrated siRNA-mediated knockdown analysis. However, all three proteins, suggesting crosstalk between canonical non-canonical signaling pathways enhances responses. These results indicate induction mediated achievable tolerated, could be infections.