Mycobacterium abscessus infection leads to enhanced production of type 1 interferon and NLRP3 inflammasome activation in murine macrophages via mitochondrial oxidative stress
Open Access
- 25 March 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 16 (3), e1008294
- https://doi.org/10.1371/journal.ppat.1008294
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. 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.Keywords
This publication has 59 references indexed in Scilit:
- Rough colony morphology of Mycobacterium massiliense Type II genotype is due to the deletion of glycopeptidolipid locus within its genomeBMC Genomics, 2013
- Mycobacterium Tuberculosis Activates the DNA-Dependent Cytosolic Surveillance Pathway within MacrophagesCell Host & Microbe, 2012
- ESX‐1‐mediated translocation to the cytosol controls virulence of mycobacteriaCellular Microbiology, 2012
- Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during ApoptosisImmunity, 2012
- Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell DeathPLoS Pathogens, 2012
- Mycobacterium abscessus: a new player in the mycobacterial fieldTrends in Microbiology, 2010
- Evidence for Pore Formation in Host Cell Membranes by ESX-1-Secreted ESAT-6 and Its Role in Mycobacterium marinum Escape from the VacuoleInfection and Immunity, 2008
- Proportions of Mycobacterium massiliense and Mycobacterium bolletii Strains among Korean Mycobacterium chelonae-Mycobacterium abscessus Group IsolatesJournal of Clinical Microbiology, 2008
- Multicenter Cross-Sectional Study of Nontuberculous Mycobacterial Infections among Cystic Fibrosis Patients, IsraelEmerging Infectious Diseases, 2008
- Hypervirulence of a Rough Variant of the Mycobacterium abscessus Type StrainInfection and Immunity, 2007