Monocyte Metabolic Reprogramming Promotes Pro-Inflammatory Activity and Staphylococcus Aureus Biofilm Clearance

Authors

Kelsey J. Yamada, University of Nebraska Medical CenterFollow
Cortney E. Heim, University of Nebraska Medical CenterFollow
Xinyuan Xi, University of Nebraska Medical CenterFollow
Kuldeep S. Attri, University of Nebraska Medical CenterFollow
Dezhen Wang, University of Nebraska Medical CenterFollow
Wenting Zhang, University of Nebraska Medical CenterFollow
Pankaj K. Singh, University of Nebraska Medical CenterFollow
Tatiana K. Bronich, University of Nebraska Medical CenterFollow
Tammy Kielian, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

PLoS Pathogens

Publication Date

2020

Volume

16

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.

DOI Link

10.1371/journal.ppat.1008354

ISSN

1553-7374

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Yamada, Kelsey J.; Heim, Cortney E.; Xi, Xinyuan; Attri, Kuldeep S.; Wang, Dezhen; Zhang, Wenting; Singh, Pankaj K.; Bronich, Tatiana K.; and Kielian, Tammy, "Monocyte Metabolic Reprogramming Promotes Pro-Inflammatory Activity and Staphylococcus Aureus Biofilm Clearance" (2020). Journal Articles: Pathology and Microbiology. 72.
https://digitalcommons.unmc.edu/com_pathmicro_articles/72