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.
Highlights
Mycobacterium abscessus (MAB) is a species of rapidly growing mycobacteria (RGM) that leads to pulmonary infection [1,2,3,4], and it has gained increasing attention worldwide as a common pathogen in lung diseases, especially in cystic fibrosis patients [5,6,7]
We found that live but not heat-killed (HK) M. abscessus strain (MAB-R) strains increased mitochondrial ROS and increased release of oxidized mitochondrial DNA into the cytosol of murine macrophages compared to the effects of live M. abscessus strain (MAB-S) strains, resulting in enhanced NLRP3 inflammasome-mediated IL-1β and cGAS-STING-dependent IFN-I production
Mitochondrial morphology in macrophages infected with a smooth type of M. abscessus strain (MAB-S) was similar to that of normal mitochondria, and the mitochondrial damage was relatively minor compared to that in cells infected with MAB-R strains (Fig 1A)
Summary
Mycobacterium abscessus (MAB) is a species of rapidly growing mycobacteria (RGM) that leads to pulmonary infection [1,2,3,4], and it has gained increasing attention worldwide as a common pathogen in lung diseases, especially in cystic fibrosis patients [5,6,7]. MAB strains lead to nosocomial infections [8, 9], and MAB infections are well known for being difficult to treat [10, 11], due to both natural broad-spectrum and acquired resistance, with disparate patterns of antibiotic susceptibility observed between different clinical strains [12,13,14,15,16]. MAB-R causes a more severe inflammatory response in infected macrophages or in infected mice compared to the effects of MAB-S strains [18, 20, 21]. MAB-S has an advantage in survival in the environment due to GPL-based biofilm formation, which contributes to its enhanced resistance to bacterial apoptotic cell death [2, 20, 21]
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