The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

Abstract

Mycobacterium abscessus is a pathogenic, rapidly growing mycobacterium responsible for pulmonary and cutaneous infections in immunocompetent patients and in patients with Mendelian disorders, such as cystic fibrosis (CF). Mycobacterium abscessus is known to transition from a smooth (S) morphotype with cell surface-associated glycopeptidolipids (GPL) to a rough (R) morphotype lacking GPL. Herein, we show that M. abscessus S and R variants are able to grow inside macrophages and are present in morphologically distinct phagosomes. The S forms are found mostly as single bacteria within phagosomes characterized by a tightly apposed phagosomal membrane and the presence of an electron translucent zone (ETZ) surrounding the bacilli. By contrast, infection with the R form leads to phagosomes often containing more than two bacilli, surrounded by a loose phagosomal membrane and lacking the ETZ. In contrast to the R variant, the S variant is capable of restricting intraphagosomal acidification and induces less apoptosis and autophagy. Importantly, the membrane of phagosomes enclosing the S forms showed signs of alteration, such as breaks or partial degradation. Although not frequently encountered, these events suggest that the S form is capable of provoking phagosome–cytosol communication. In conclusion, M. abscessus S exhibits traits inside macrophages that are reminiscent of slow-growing mycobacterial species.

Autophagy inMycobacterium abscessusInfection

“…However, there is not much information on the machanisms by which R and S types induce distinct autophagosome formation. Recently, it was demonstrated that the R type induces more autophagy than the S variant, as evidenced by the increased percentage of LC3 formation in infected cells (80). This was in accordance with the study conducted in our lab using the R type clinical isolate, UC22…”

“…Thus, cording has a crucial role in the pathophysiology of M. abscessus infection as it is a mechanism of immune evasion. The intraphagosomal R and S strains display distinct morphology as the S strain exhibits a thick outermost electron transluscent zone (ETZ) which is apposed to the phagosome membrane all around while the R form produces a very thin ETZ (80).…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…In one study, azithromycin appeared to impair autophagic and phagosomal degradation resulting in decreased mycobacterial clearance (including M. abscessus ) by preventing lysosomal acidification and intracellular killing [184]. The smooth morphotype of M. abscessus was also recently shown to restrict intraphagosomal acidification resulting in reduced apoptosis and autophagy [185]. However, a detailed understanding of autophagy and/or inflammasome pathways as drivers of intracellular persistence and pathogenesis in NTM is still undefined and crosstalk between the two pathways is unknown.…”

The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection

“…Indeed, infection of classical immunocompetent mouse models leads to transient colonization, thus impeding their use as a valuable animal models to study chronic disease and the in vivo therapeutic efficacy of drugs (Bernut et al, 2014b). However, in the past few years the development of multiple cellular, non-mammalian and mammalian models have helped to study the chronology and the pathology of Mabs infection (Byrd and Lyons, 1999; Howard et al, 2006; Ordway et al, 2008; Oh et al, 2013; Bernut et al, 2014a; Bakala N'Goma et al, 2015; Roux et al, 2016). Among these new model systems, a few have been validated for their suitability for in vivo drug efficacy studies against Mabs (Ordway et al, 2008; Lerat et al, 2014; Oh et al, 2014; Bernut et al, 2014b).…”

“…A major hallmark of Mabs R is its high propensity to aggregate, leading to the formation of phagocytic cups and the presence of social phagosomes containing usually more than one bacillus. These phagocytic cups and bacterial laden phagosomes are associated with increased cell mortality, evoking a typical trait of RGM (Brambilla et al, 2016; Roux et al, 2016). In contrast, loner phagosomes containing one bacilli are usually found within macrophages infected with the S form (Figure 1).…”