Modeling Nontuberculous Mycobacterial Disease in Xenopus laevis

The global incidence of diseases caused by Mycobacterium abscessus (Mab), which is a nontuberculous mycobacterium (NTM), is increasing, driven by improved diagnostics and environmental changes that disrupt natural reservoirs in soil and water. These disruptions facilitate contamination of water systems. Immunocompromised individuals, particularly those with cystic fibrosis or chronic obstructive pulmonary disease, are at elevated risk, although Mab can also infect otherwise healthy individuals, causing pulmonary and cutaneous disease. Clinical management remains challenging due to intrinsic antibiotic resistance and the limited efficacy of standard anti-tuberculosis regimens. Despite this growing burden, the mechanisms governing Mab persistence and pathogenesis remain poorly defined. Progress has been constrained by the limitations of existing animal models. Mice typically clear infections rapidly, even when immunocompromised, limiting studies of chronic disease. Zebrafish support persistent infection but lack lungs and have a less developed adaptive immune system. These limitations highlight the need for alternative models. Here, we present a perspective highlighting the amphibian Xenopus laevis as a complementary model for investigating Mab chronic infection and disease. X. laevis tadpoles develop functional lungs early and possess conserved innate and adaptive immune components, including macrophages and antigen presentation pathways. Their external development allows precise control of environmental exposures and accessibility to experimentation, such as live imaging, to study Mab infection over 50 days. Xenopus models combine the experimental accessibility of early developmental stages, genetic and transgenic tractability, and established protocols for animal husbandry and mycobacterial that are characteristic of zebrafish, with the conserved lung architecture of mammals. We discuss the application of Xenopus models to investigate the potential role of a novel putative secondary metabolite gene cluster (SMGC) hypothesized to encode a virulence factor that promotes Mab colonization, interaction with macrophages, and persistence. Collectively, these features establish X. laevis tadpoles as a valuable experimental platform for dissecting host–pathogen interactions and for identifying potential targets for therapeutic intervention.