Abstract
Biofilm-associated prosthetic joint infections (PJIs) cause significant morbidity due to their recalcitrance to immune-mediated clearance and antibiotics, with Staphylococcus aureus (S. aureus) among the most prevalent pathogens. We previously demonstrated that S. aureus biofilm-associated monocytes are polarized to an anti-inflammatory phenotype and the adoptive transfer of pro-inflammatory macrophages attenuated biofilm burden, highlighting the critical role of monocyte/macrophage inflammatory status in dictating biofilm persistence. The inflammatory properties of leukocytes are linked to their metabolic state, and here we demonstrate that biofilm-associated monocytes exhibit a metabolic bias favoring oxidative phosphorylation (OxPhos) and less aerobic glycolysis to facilitate their anti-inflammatory activity and biofilm persistence. To shift monocyte metabolism in vivo and reprogram cells to a pro-inflammatory state, a nanoparticle approach was utilized to deliver the OxPhos inhibitor oligomycin to monocytes. Using a mouse model of S. aureus PJI, oligomycin nanoparticles were preferentially internalized by monocytes, which significantly reduced S. aureus biofilm burden by altering metabolism and promoting the pro-inflammatory properties of infiltrating monocytes as revealed by metabolomics and RT-qPCR, respectively. Injection of oligomycin alone had no effect on monocyte metabolism or biofilm burden, establishing that intracellular delivery of oligomycin is required to reprogram monocyte metabolic activity and that oligomycin lacks antibacterial activity against S. aureus biofilms. Remarkably, monocyte metabolic reprogramming with oligomycin nanoparticles was effective at clearing established biofilms in combination with systemic antibiotics. These findings suggest that metabolic reprogramming of biofilm-associated monocytes may represent a novel therapeutic approach for PJI.
Highlights
The frequency of orthopedic procedures, such as total knee and total hip arthroplasty (TKA and THA, respectively), continues to increase and is predicted to reach an annual rate in the United States by 2030 of 572,000 and 3.48 million, respectively [1]
S. aureus biofilm infection promotes a shift towards oxidative phosphorylation (OxPhos) metabolism in monocytes
Previous work from our laboratory using a mouse model of S. aureus prosthetic joint infections (PJIs) has shown that biofilms promote monocyte anti-inflammatory activity [12,13,14]
Summary
The frequency of orthopedic procedures, such as total knee and total hip arthroplasty (TKA and THA, respectively), continues to increase and is predicted to reach an annual rate in the United States by 2030 of 572,000 and 3.48 million, respectively [1]. The current standard-of-care for PJIs includes removal of the infected hardware, placement of an antibiotic-impregnated polymethylmethacrylate spacer for 4–6 weeks until the infection has resolved, followed by a second surgery to insert a new prosthesis [3,4,5]. This demonstrates the importance of developing novel therapeutic approaches to treat biofilm-associated infections without requiring multiple surgical interventions. We have demonstrated that G-MDSCs are integral to S. aureus biofilm establishment and persistence and polarize infiltrating monocytes towards an anti-inflammatory phenotype [12,13,14,15].
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