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Mycobacterium abscessus infection leads to enhanced production of type 1 interferon and NLRP3 inflammasome activation in murine macrophages via mitochondrial oxidative stress
- Source :
- PLoS Pathogens, Vol 16, Iss 3, p e1008294 (2020), PLoS Pathogens
- Publication Year :
- 2020
- Publisher :
- Public Library of Science (PLoS), 2020.
-
Abstract
- Mycobacterium abscessus (MAB) is a rapidly growing mycobacterium (RGM), and infections with this pathogen have been increasing worldwide. Recently, we reported that rough type (MAB-R) but not smooth type (MAB-S) strains enhanced type 1 interferon (IFN-I) secretion via bacterial phagosome escape, contributing to increased virulence. Here, we sought to investigate the role of mitochondrial oxidative stress in bacterial survival, IFN-I secretion and NLRP3 inflammasome activation in MAB-infected murine macrophages. We found that live but not heat-killed (HK) MAB-R strains increased mitochondrial ROS (mtROS) and increased release of oxidized mitochondrial DNA (mtDNA) into the cytosol of murine macrophages compared to the effects of live MAB-S strains, resulting in enhanced NLRP3 inflammasome-mediated IL-1β and cGAS-STING-dependent IFN-I production. Treatment of the infected macrophages with mtROS-modulating agents such as mito-TEMPO or cyclosporin A reduced cytosolic oxidized mtDNA, which inhibited the MAB-R strain-induced production of IL-1β and IFN-I. The reduced cytosolic oxidized mtDNA also inhibited intracellular growth of MAB-R strains via cytosolic escape following phagosomal rupture and via IFN-I-mediated cell-to-cell spreading. Moreover, our data showed that mtROS-dependent IFN-I production inhibited IL-1β production, further contributing to MAB-R intracellular survival in murine macrophages. In conclusion, our data indicated that MAB-R strains enhanced IFN-I and IL-1β production by inducing mtROS as a pathogen-associated molecular pattern (PAMP). These events also enhance bacterial survival in macrophages and dampen inflammation, which contribute to the pathogenesis of MAB-R strains.<br />Author summary MAB infections have gained increasing attention due to their clinical significance. Mitochondrial oxidative stress regulates intrinsic innate immune responses mainly via IFN-I or IL-1β production, which affects the pathogenesis of several pathogens, including Mycobacterium tuberculosis infections. Here, we found that virulent MAB-R but not MAB-S strains induced mtROS in infected macrophages, resulting in enhanced IFN-I and IL-1β production by the release of oxidized mtDNA into the cytosol. Furthermore, increased mtROS exerted a pro-bacterial effect by inducing IFN-I-mediated escape of MAB-R into the cytosol. In MAB-R-infected murine macrophages, mtROS-induced IFN-I also inhibited IL-1β production exerting an antibacterial effect, further contributing to intracellular bacterial survival. Our data indicate that mtROS play an important role in MAB-R pathogenesis by facilitating bacterial survival and dampening inflammation in macrophages as a kind of specific class of PAMP. mtROS may be a valuable target for the treatment of virulent MAB infections.
- Subjects :
- Male
Mitochondrial ROS
Inflammasomes
Interleukin-1beta
Mitochondrion
Mycobacterium abscessus
Pathology and Laboratory Medicine
Biochemistry
Mice
White Blood Cells
Cytosol
Animal Cells
Phagosomes
Cyclosporin a
Medicine and Health Sciences
Biology (General)
Energy-Producing Organelles
Phagosome
0303 health sciences
Immune System Proteins
biology
Chemistry
030302 biochemistry & molecular biology
Mitochondrial DNA
Mitochondria
Bacterial Pathogens
Nucleic acids
Actinobacteria
Intracellular Pathogens
Medical Microbiology
Cellular Types
Cellular Structures and Organelles
Pathogens
Intracellular
Research Article
Forms of DNA
QH301-705.5
Immune Cells
Immunology
Mycobacterium Infections, Nontuberculous
Bioenergetics
Microbiology
03 medical and health sciences
Virology
NLR Family, Pyrin Domain-Containing 3 Protein
Genetics
Animals
Humans
Secretion
Vesicles
Microbial Pathogens
Molecular Biology
030304 developmental biology
Blood Cells
Bacteria
Macrophages
Intracellular parasite
Organisms
Biology and Life Sciences
Proteins
Mycobacteria
Interferon-beta
Cell Biology
DNA
RC581-607
biology.organism_classification
Mice, Inbred C57BL
Oxidative Stress
Parasitology
Immunologic diseases. Allergy
Reactive Oxygen Species
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 16
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....5facea61ec15300e63899ac8164412de