A novel rapid host cell entry pathway determines the intracellular fate of Staphylococcus aureus

Staphylococcus aureus is an opportunistic pathogen causing severe diseases. Recently, S. aureus was recognized as an intracellular pathogen, whereby the intracellular niche promotes immune evasion and antibiotic resistance. Interaction of S. aureus with versatile host cell receptors was described previously, suggesting that internalization of the pathogen can occur via several pathways. It remains elusive whether the pathway of internalization can affect the intracellular fate of the bacteria. Here, we identified a mechanism governing cellular uptake of S. aureus which relies on lysosomal Ca²⁺, lysosomal exocytosis, and occurs concurrently to other well-known entry pathways within the same host cell population. This internalization pathway is rapid and active within only a few minutes after bacterial contact with host cells. Compared to slow bacterial internalization, the rapid pathway demonstrates altered phagosomal maturation as well as translocation of the pathogen to the host cytosol and ultimately results in different rates of intracellular bacterial replication and host cell death. We show that these alternative infection outcomes are caused by the mode of bacterial uptake.