S. aureus Evades Macrophage Killing through NLRP3-Dependent Effects on Mitochondrial Trafficking

Cell Rep. 2018 Feb 27;22(9):2431-2441. doi: 10.1016/j.celrep.2018.02.027.


Clinical severity of Staphylococcus aureus respiratory infection correlates with alpha toxin (AT) expression. AT activates the NLRP3 inflammasome; deletion of Nlrp3, or AT neutralization, protects mice from lethal S. aureus pneumonia. We tested the hypothesis that this protection is not due to a reduction in inflammasome-dependent cytokines (IL-1β/IL-18) but increased bactericidal function of macrophages. In vivo, neutralization of AT or NLRP3 improved bacterial clearance and survival, while blocking IL-1β/IL-18 did not. Primary human monocytes were used in vitro to determine the mechanism through which NLRP3 alters bacterial killing. In cells treated with small interfering RNA (siRNA) targeting NLRP3 or infected with AT-null S. aureus, mitochondria co-localize with bacterial-containing phagosomes. Mitochondrial engagement activates caspase-1, a process dependent on complex II of the electron transport chain, near the phagosome, promoting its acidification. These data demonstrate a mechanism utilized by S. aureus to sequester itself from antimicrobial processes within the cell.

Keywords: NLRP3 inflammasome; S. aureus; alpha toxin; bacterial infection; mitochondria; monoclonal antibody; pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins
  • Caspase 1 / metabolism
  • Electron Transport Complex II / metabolism
  • Female
  • Hemolysin Proteins
  • Humans
  • Immune Evasion*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / microbiology*
  • Mice, Inbred C57BL
  • Microbial Viability*
  • Mitochondria / metabolism*
  • Monocytes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Neutralization Tests
  • Protein Transport
  • Reactive Oxygen Species / metabolism
  • Staphylococcus aureus / metabolism*


  • Bacterial Toxins
  • Hemolysin Proteins
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • staphylococcal alpha-toxin
  • Electron Transport Complex II
  • Caspase 1