Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome

J Infect Dis. 2012 Mar 1;205(5):807-17. doi: 10.1093/infdis/jir846. Epub 2012 Jan 25.

Abstract

Staphylococcus aureus is a dangerous pathogen that can cause necrotizing infections characterized by massive inflammatory responses and tissue destruction. Staphylococcal α-hemolysin is an essential virulence factor in severe S. aureus pneumonia. It activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome to induce production of interleukin-1β and programmed necrotic cell death. We sought to determine the role of α-hemolysin-mediated activation of NLRP3 in the pathogenesis of S. aureus pneumonia. We show that α-hemolysin activates the NLRP3 inflammasome during S. aureus pneumonia, inducing necrotic pulmonary injury. Moreover, Nlrp3(-/-) mice have less-severe pneumonia. Pulmonary injury induced by isolated α-hemolysin or live S. aureus is independent of interleukin-1β signaling, implicating NLRP3-induced necrosis in the pathogenesis of severe infection. This work demonstrates the exploitation of host inflammatory signaling by S. aureus and suggests the NLRP3 inflammasome as a potential target for pharmacologic interventions in severe S. aureus infections.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Toxins / metabolism*
  • Bacterial Toxins / pharmacology
  • CD11b Antigen
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Disease Models, Animal
  • Hemolysin Proteins / metabolism*
  • Hemolysin Proteins / pharmacology
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism*
  • Kaplan-Meier Estimate
  • Lung / pathology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Necrosis / microbiology
  • Pneumonia, Staphylococcal / microbiology*
  • Signal Transduction
  • Staphylococcus aureus / genetics*
  • Staphylococcus aureus / metabolism
  • Staphylococcus aureus / pathogenicity*

Substances

  • Bacterial Toxins
  • CD11b Antigen
  • Carrier Proteins
  • Hemolysin Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • staphylococcal alpha-toxin