Intracellular Staphylococcus aureus in human infections: evidence from clinical specimens

Staphylococcus aureus is a major human pathogen causing extensive morbidity and mortality. In vitro and animal studies show that S aureus can invade and survive within host cells. Such intracellular reservoirs might impair antibiotic and immune clearance, yet their clinical relevance in humans remains controversial. Here, we review 33 human studies published between 1984 and 2025 that assess the occurrence of intracellular S aureus across diverse disease conditions. We critically evaluated the methods used to detect intracellular S aureus in human biopsies and evidence across different tissues and diseases. Although the strength of evidence varies across studies, the overall findings strongly suggest the presence of S aureus within diverse human cell types. These findings could have important implications for diagnosis, treatment, and prevention. We identify key knowledge gaps, including the relative proportions of intracellular and extracellular S aureus, viability of intracellular bacteria, and persistence of these bacteria during antibiotic exposure. Thus, our analysis highlights intracellular states as a relevant part of S aureus biology in human infections and identifies future research directions.