Abstract
Mycobacterium abscessus complex (MAB) is a rapidly growing mycobacterium(RGM) whose clinical significance as an emerging human pathogen has been increasing worldwide. It has two types of colony morphology, a smooth (S) type, producing high glycopeptidolipid (GPL) content, and a rough (R) type, which produces low levels of GPLs and is associated with increased virulence. However, the mechanism responsible for their difference in virulence is poorly known. By ultrastructural examination of murine macrophages infected, we found that MAB-R strains could replicate more actively in the macrophage phagosome than the S variants and that they could escape into cytosol via phagosomal rupture. The cytosolic access of MAB-R strains via phagosomal rupture led to enhanced Type I interferon (IFN) production and cell death, which resulted in their cell-to-cell spreading. This behavior can provide an additional niche for the survival of MAB-R strains. In addition, we found that their enhancement of cell death mediated cell spreading are dependent on Type I IFN signaling via comparison of wild-type and IFNAR1 knockout mice. In conclusion, our data indicated that a transition of MAB-S strains into MAB-R variants increased their virulence via enhanced Type I IFN production, which led to enhanced survival in infected macrophage via cell death mediated cell-to-cell spreading. This result provides not only a novel insight into the difference in virulence between MAB-R and -S variants but also hints to their treatment strategy.
Highlights
Mycobacterium abscessus complex (MAB) is recognized as a major pathogen leading to pulmonary infection within the rapidly growing mycobacteria (RGMs) [1,2,3] and is a common pathogen in lung diseases, especially in cystic fibrosis patients [4,5,6]
We evaluated the intracellular growth (Figures 1A–C) and pro(TNF-α and IL-6) and anti- (IL-10) inflammatory cytokine secretion (Figures 1D–F) of MAB-R and -S strains of various subspecies or genotypes [S-Abs smooth strains (S-Abs_S): M. abscessus type strain ATCC 19977 smooth strain, Asan 53040, and Asan 58582; S-Abs rough strains (S-Abs_R): M. abscessus type strain ATCC 19977 rough strain, Asan 52550 and Asan 58116; species M. massiliense (S-Mas) type I-Smooth (S-Mas_I-S): type strain, Asan 15, Asan 51312, and Asan 51843; S-Mas type I-Rough (S-Mas_IR): Asan 16, Asan 22, and Asan 34; and S-Mas type II-Rough (S-Mas_II-R): Asan 4, Asan 50594, and Asan 62188] in murine macrophage J774A.1 cells (1 × 106 cells) as a function of the 10 multiplicity of infection (M.O.I.) (1 × 107 bacteria) (Figures 1A,B)
The results showed that irrespective of subspecies or genotypes, MAB-R strains formed significantly higher levels of colony-forming unit (CFU) than MAB consists of two phenotypes: smooth colony (MAB-S) strains in J774A.1 cells
Summary
Mycobacterium abscessus complex (MAB) is recognized as a major pathogen leading to pulmonary infection within the rapidly growing mycobacteria (RGMs) [1,2,3] and is a common pathogen in lung diseases, especially in cystic fibrosis patients [4,5,6]. MAB is one of the major pathogens leading to nosocomial infections [9]. MAB consists of diverse subspecies or genotypes. The MAB group can be divided into two subspecies, M. abscessus subsp. Abscessus (hereafter, S-Abs) and M. abscessus subsp. S-Mas can be further subdivided into two hsp genotypes (Type I and Type II) [14]
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