LAUSR

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading global cause of death from an infectious agent. Mycobacteria thrive within their host Mϕs and presently, there is no animal model that permits combined in vitro and in vivo study of mycobacteria‐host Mϕ interactions. Mycobacterium marinum (Mm), which causes TB in aquatic vertebrates, has become a promising model for TB research, owing to its close genetic relatedness to Mtb and the availability of alternative, natural host aquatic animal models. Here, we adopted the Xenopus laevis frog‐Mm surrogate infection model to study host Mϕ susceptibility and resistance to mycobacteria. Mϕ differentiation is regulated though the CSF‐1 receptor (CSF‐1R), which is activated by CSF‐1 and the unrelated IL‐34 cytokines. Using combined in vitro and in vivo approaches, we demonstrated that CSF‐1‐Mϕs exacerbate Mm infections, are more susceptible to mycobacterial entry and are less effective at killing this pathogen. By contrast, IL‐34‐Mϕs confer anti‐Mm resistance in vivo, are less susceptible to Mm entry and more effectively eliminate internalized mycobacteria. Moreover, we showed that the human CSF‐1‐ and IL‐34‐Mϕs are likewise, respectively, susceptible and resistant to mycobacteria, and that both frog and human CSF‐1‐Mϕs are more prone to the spread of mycobacteria and to being infected by Mm‐laden Mϕs than the respective IL‐34‐Mϕ subsets. This work marks the first report describing the roles of these Mϕ subsets in mycobacterial disease and may well lead to the development of more targeted anti‐Mtb approaches.