Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular

PLoS Pathog. 2015 Jun 12;11(6):e1004970. doi: 10.1371/journal.ppat.1004970. eCollection 2015 Jun.


Staphylococcus aureus infections are a growing health burden worldwide, and paramount to this bacterium's pathogenesis is the production of virulence factors, including pore-forming leukotoxins. Leukocidin A/B (LukAB) is a recently discovered toxin that kills primary human phagocytes, though the underlying mechanism of cell death is not understood. We demonstrate here that LukAB is a major contributor to the death of human monocytes. Using a variety of in vitro and ex vivo intoxication and infection models, we found that LukAB activates Caspase 1, promotes IL-1β secretion and induces necrosis in human monocytes. Using THP1 cells as a model for human monocytes, we found that the inflammasome components NLRP3 and ASC are required for LukAB-mediated IL-1β secretion and necrotic cell death. S. aureus was shown to kill human monocytes in a LukAB dependent manner under both extracellular and intracellular ex vivo infection models. Although LukAB-mediated killing of THP1 monocytes from extracellular S. aureus requires ASC, NLRP3 and the LukAB-receptor CD11b, LukAB-mediated killing from phagocytosed S. aureus is independent of ASC or NLRP3, but dependent on CD11b. Altogether, this study provides insight into the nature of LukAB-mediated killing of human monocytes. The discovery that S. aureus LukAB provokes differential host responses in a manner dependent on the cellular contact site is critical for the development of anti-infective/anti-inflammatory therapies that target the NLRP3 inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / metabolism*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Cytoskeletal Proteins / metabolism*
  • Extracellular Space / metabolism*
  • Flow Cytometry
  • Host-Parasite Interactions / physiology*
  • Humans
  • Immunoassay
  • Immunoblotting
  • Intracellular Space / metabolism
  • Leukocidins / metabolism*
  • Microscopy, Electron, Transmission
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Staphylococcal Infections / metabolism*
  • Staphylococcus aureus / metabolism
  • Virulence Factors / physiology*


  • Bacterial Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Leukocidins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Virulence Factors
  • leukocidin AB, Staphylococcus aureus