Intracellular survival and escape from within macrophages by Staphylococcus aureus

Abstract

The human pathogen Staphylococcus aureus is considered mainly as an extracellular, opportunistic pathogen, that causes a diverse range of illnesses worldwide. However, S. aureus employs different strategies to evade the host immune response and is able to survive within and escape from host cells, including macrophages. An agr/sae-mutant of strain USA300 is unable to escape from human macrophages but can replicate and survive within macrophages.

This study investigates whether this "non-toxic" S. aureus resembles less pathogenic coagulase-negative Staphylococcal species (CoNS) such as S. carnosus, S. lugdunensis, S. capitis, S. warneri, and S. pettenkoferi. We found that CoNS are more efficiently killed by macrophage-like THP-1 cells or human primary macrophages. While deletion of superoxide dismutases impaired S. aureus survival in primary macrophages, it did not affect survival in THP-1 cells. Expression of S. aureus-specific sodM in S. epidermidis was insufficient to protect against killing, indicating that better survival of S. aureus is not solely due to higher protection from reactive oxygen species (ROS). Notably, "non-toxic" S. aureus was insensitive to pH, whereas most CoNS were protected from phagosomal acidification. Furthermore, S. aureus can induce a previously unknown type of cell death in macrophages, with Leukocidin A/B (LukAB) playing a critical role in cell exit and host cell death. Exogenous LukAB triggers activation of the NLRP3 inflammasome, promotes IL-1ß secretion, and kills primary human monocytes. However, the intracellular role of LukAB and its effects on cell death pathways and the NLRP3 inflammasome remain unclear. Using different S. aureus strains lacking LukAB and/or with inducible LukAB expression, we discovered a decoupling of NLRP3 inflammasome activation and cell death via a non-pyroptotic route. This process depends on the CD11b receptor for intracellular LukAB but does not involve classical apoptosis or necroptosis, despite the activation of known signaling mediators. Thus, S. aureus LukAB induces a non-conventional cell death pathway in human macrophages.

Die Dissertation ist gesperrt bis zum 15. Juni 2026 !