Exploring the Role of a Putative Secondary Metabolite Biosynthesis Pathway in Mycobacterium abscessus Pathogenesis Using a Xenopus laevis Tadpole Model

• Published in: Microorganisms (Basel) Vol. 12; no. 6; p. 1120
• Main Authors: Miller, Nicholas James, Dimitrakopoulou, Dionysia, Baglia, Laurel A, Pavelka, Jr, Martin S, Robert, Jacques
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.05.2024; MDPI
• Subjects: Animal models; Animals; Antibiotics; Bacteria; Bacterial infections; Biosynthesis; comparative immunology; Confocal microscopy; Cystic fibrosis; Experiments; Frogs; Gene deletion; Gene expression; Genomes; Glycerol; Health aspects; Immunopathogenesis; Infection; Infections; Inflammation; Inoculation; intravital microscopy; Juveniles; Lung diseases; Lungs; Lymphocytes; Lymphocytes T; macrophage recruitment; Macrophages; Metabolites; Microscopy; Mutants; Mycobacterium abscessus; Nitric-oxide synthase; Pathogenesis; Pathogens; Secondary metabolites; Streptonigrin; Tumor necrosis factor-α; Virulence; Wound infection; Xenopus; Xenopus laevis; γ-Interferon; United States > US; Xenopus; macrophage recruitment; intravital microscopy; comparative immunology
• ISSN: 2076-2607; 2076-2607
• DOI: 10.3390/microorganisms12061120

is an emerging human pathogen that has a high rate of incidence in immunocompromised individuals. We have found a putative secondary metabolite pathway within , which may be a key factor in its pathogenesis. This novel pathway is encoded in a gene cluster spanning MAB_0284c to 0305 and is related to pathways, producing the secondary metabolites streptonigrin and nybomycin. We constructed an in-frame deletion of the MAB_0295 ( ) gene and tested it in our animal model. We have previously shown that tadpoles, which have functional lungs and T cells, can serve as a reliable comparative model for persistent infection and pathogenesis. Here, we report that tadpoles intraperitoneally infected with the ∆ mutant exhibit early decreased bacterial loads and significantly increased survival compared with those infected with WT . ∆ mutant also induced lower transcript levels of several pro-inflammatory cytokines ( , , , ) than those of WT in the liver and lungs. In addition, there was impaired macrophage recruitment and decreased macrophage infection in tadpoles infected with the ∆ mutant, by tail wound inoculation, compared to those infected with the WT bacteria, as assayed by intravital confocal microscopy. These data underline the relevance and usefulness of tadpoles as a novel comparative animal model to identify genetic determinants of immunopathogenesis, suggesting a role for this novel and uncharacterized pathway in pathogenesis and macrophage recruitment.