Staphylococcus aureus inhibits the NLRP3 inflammasome in macrophages during the early phases of intracellular infection, but not the late phases

Staphylococcus aureus ( S. aureus ) is a highly virulent pathogen responsible for chronic infections such as osteomyelitis. Although its interaction with the host immune system has been widely studied, the specific role of inflammasomes in regulating the infection within macrophages remains unclear. We investigated this question using bone marrow-derived macrophages infected with S. aureus and observed a significant reduction in intracellular bacterial load beginning at 18 hours post-infection (hpi), which continued through 96 hpi. Notably, robust activation of the NLRP3 inflammasome—including inflammasome assembly, IL-1β and GSDMD maturation, and pyroptosis—occurred only after 18 hpi. This led us to hypothesize that S. aureus suppresses inflammasome activation during early infection. Supporting this, infected BMDMs failed to respond robustly to LPS and nigericin up to 18 hpi, with partial recovery at later timepoints, suggesting that S. aureus initially inhibits NLRP3 signaling to persist within macrophages but is later counteracted by the host response.