A niche-specific role for ArlRS enables Staphylococcus aureus growth within Kupffer cells

Staphylococcus aureus bloodstream infections pose significant health risks, despite antibiotic treatment. Previous research revealed Kupffer cells (KCs), a type of liver macrophage, as the main defenders against circulating S. aureus. Nevertheless, some bacteria manage to survive within these cells and trigger systemic infection. By employing advanced imaging techniques, scientists have now uncovered the role of a specific bacterial signaling system in the survival of S. aureus within KCs.

Using spinning-disk intravital and super-resolution microscopy, researchers observed that bacterial two-component system (TCS) signaling is essential for intracellular replication in KCs. A strain of S. aureus lacking all non-essential TCSs failed to replicate within KCs, forming only single organisms. These bacteria exhibited reduced dissemination, kidney abscess formation, and lower virulence, leading to improved host survival. Restoring the arlRS gene in the mutant strain returned the bacteria to a wild-type state.

The defect in intracellular replication was not observed in primary or cultured macrophages, suggesting that ArlRS-dependent replication is highly specific to KCs and not replicated in conventional in vitro models. Moreover, restricting KC residency with vancomycin treatment after infection further decreased renal infection by the arlRS-deficient bacteria.

These findings emphasize the critical role of ArlRS in intracellular replication within KCs and propose the KC intracellular reservoir as a vital driver of S. aureus pathogenesis and a promising therapeutic target during bloodstream infections.