Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival

Staphylococcus aureus propensity for intracellular survival presents a challenge to effectively treat infection, with significant evidence suggesting S. aureus can hijack phagocytes for host dissemination, worsening clinical outcomes. Human polymorphonuclear neutrophils (hPMN) have been identified as an important conduit for the intracellular survival of S. aureus, yet this immune evasion mechanism remains incompletely understood. Multiplex gene expression analysis was used to profile the gene expression of hPMN harboring intracellular S. aureus and found that the anti-inflammatory adenosine receptor, adora2a (A2aR), was upregulated along with several A2aR- associated genes. Importantly, treatment with the A2aR inhibitor, ZM-241385, reduced intracellular survival of S. aureus within hPMN while enhancing ROS production and neutrophil extracellular traps. This suggests that S. aureus uses A2aR to dampen hPMN effector functions as a mechanism to boost intracellular survival. A2aR inhibition led to a metabolic switch from glycolysis to the pentose phosphate pathway (PPP) in hPMN, which facilitated an increase in NADPH levels and reactive oxygen species (ROS) production. Taken together, our work highlights the importance of the A2aR, which is targeted by S. aureus to suppress the PPP, limiting ROS production, and thus creating a more hospitable intracellular niche in which to survive.