Mitochondria-Derived Vesicles Deliver Antimicrobial Reactive Oxygen Species to Control Phagosome-Localized Staphylococcus aureus

Cell Host Microbe. 2018 Nov 14;24(5):625-636.e5. doi: 10.1016/j.chom.2018.10.005. Epub 2018 Oct 25.

Abstract

Pathogenic bacteria taken up into the macrophage phagosome are the target of many anti-microbial mechanisms. Although mitochondria-derived antimicrobial effectors like reactive oxygen species (mROS) aid in bacterial killing, it is unclear how these effectors reach bacteria within the phagosomal lumen. We show here that endoplasmic reticulum stress triggered upon methicillin-resistant Staphylococcus aureus (MRSA) infection induces mROS that are delivered to bacteria-containing phagosomes via mitochondria-derived vesicles (MDVs). The endoplasmic reticulum stress sensor IRE1α induces mROS, specifically hydrogen peroxide (mH2O2), upon MRSA infection. MRSA infection also stimulates the generation of MDVs, which require the mitochondrial stress response factor Parkin, and contributes to mH2O2 accumulation in bacteria-containing phagosomes. Accumulation of phagosomal H2O2 requires Toll-like receptor signaling and the mitochondrial enzyme superoxide dismutase-2 (Sod2), which is delivered to phagosomes by MDVs. Sod2 depletion compromises mH2O2 production and bacterial killing. Thus, mitochondrial redox capacity enhances macrophage antimicrobial function by delivering mitochondria-derived effector molecules into bacteria-containing phagosomes.

Publication types

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

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Infective Agents / pharmacology*
  • Drug Delivery Systems / methods*
  • Endoplasmic Reticulum
  • Endoribonucleases / metabolism
  • Female
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Macrophages / microbiology
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbial Viability
  • Mitochondria / metabolism*
  • NADPH Oxidase 2 / genetics
  • Oxidation-Reduction
  • Phagosomes / microbiology*
  • Protein Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / pharmacology*
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects*
  • Stress, Physiological
  • Superoxide Dismutase / metabolism
  • Toll-Like Receptors / metabolism
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Reactive Oxygen Species
  • Toll-Like Receptors
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • ERN1 protein, human
  • PTEN-induced putative kinase
  • Protein Serine-Threonine Kinases
  • Endoribonucleases