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Mitochondria-Derived Vesicles Deliver Antimicrobial Reactive Oxygen Species to Control Phagosome-Localized
Basel H Abuaita1, Tracey L Schultz1, Mary X O'Riordan1
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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.
Insights
Endoplasmic reticulum stress during Staphylococcus aureus infection triggers mitochondria-derived vesicles (MDVs) to deliver antimicrobial hydrogen peroxide (H2O2) to phagosomes, enhancing bacterial killing by macrophages.
Area of Science:
- Cellular Microbiology
- Immunology
- Mitochondrial Biology
Background:
- Macrophages engulf pathogenic bacteria into phagosomes, where they are targeted by antimicrobial mechanisms.
- Mitochondria produce antimicrobial effectors like mitochondria-derived reactive oxygen species (mROS), but their delivery to phagosomes is unclear.
- Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a significant challenge to host defense mechanisms.
Purpose of the Study:
- To elucidate the mechanism by which mitochondria-derived antimicrobial effectors reach bacteria within macrophage phagosomes.
- To investigate the role of endoplasmic reticulum stress in mediating the delivery of mROS to phagosomes during MRSA infection.
Main Methods:
- Induction of endoplasmic reticulum stress in macrophages upon MRSA infection.
- Analysis of mitochondria-derived vesicle (MDV) formation and cargo.
- Assessment of hydrogen peroxide (H2O2) accumulation in phagosomes.
- Utilized genetic depletion of key factors like Parkin and superoxide dismutase-2 (Sod2).
Main Results:
- MRSA infection triggers endoplasmic reticulum stress, leading to the production of mROS, specifically H2O2.
- Endoplasmic reticulum stress induces the formation of MDVs, dependent on the mitochondrial stress factor Parkin.
- MDVs deliver H2O2 and Sod2 to bacteria-containing phagosomes, requiring Toll-like receptor signaling for H2O2 accumulation.
- Sod2 depletion impairs H2O2 production and bacterial killing, highlighting its critical role.
Conclusions:
- Mitochondria-derived vesicles act as a conduit for delivering antimicrobial effectors like H2O2 to phagosomes during MRSA infection.
- Endoplasmic reticulum stress and the IRE1α pathway are crucial for initiating this mitochondria-macrophage communication.
- Mitochondrial redox capacity, through MDV-mediated delivery of Sod2, significantly enhances macrophage antimicrobial function.
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