MACROPHAGE DIFFERENTIATION CRITICALLY DEFINES SUSCEPTIBILITY AND RESISTANCE TO MYCOBACTERIA: NEW INSIGHTS FROM AN AMPHIBIAN MODEL

04 Jun 2019
11:20 - 11:40

MACROPHAGE DIFFERENTIATION CRITICALLY DEFINES SUSCEPTIBILITY AND RESISTANCE TO MYCOBACTERIA: NEW INSIGHTS FROM AN AMPHIBIAN MODEL

Leon Grayfer, George Washington University

Milan Popovic1, Amulya Yaparla1, Dominic Paquin-Proulx2, Daphne V. Koubourli1, Rose Webb3, Marcia Firmani4, Leon Grayfer1

1Department of Biological Sciences, 2Department of Microbiology, Immunology & Tropical Medicine, 3Pathology Core Laboratory, 4Department of Biomedical Laboratory Sciences, George Washington University, Washington, DC 20052, USA

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
macrophages (Ms) and presently there is no animal model that permits combined in vitro and in vivo study of mycobacteria-host M interactions. Mycobacterium marinum (Mm), which causes tuberculosis in aquatic vertebrates, has become an auspicious model for TB research, owing to its close genetic relatedness to Mtb and the availability of alternative, natural host aquatic animal models. We adopted the Xenopus laevis frog-Mm surrogate infection model to study host M susceptibility and resistance to mycobacteria. M differentiation is regulated though the colonystimulating factor-1 receptor (CSF-1R), which is activated by CSF-1 and the unrelated interleukin-34 (IL-34) cytokines. Using combined in vitro and in vivo approaches, we demonstrated that CSF-1-Ms exacerbate Mm infections, are more susceptible to mycobacterial entry and are less effective at killing this pathogen. By contrast, IL-34-Ms 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-Ms are likewise respectively susceptible and resistant to mycobacteria, and that both frog and human CSF-1-Ms are more prone to the spread of mycobacteria and to being infected by Mm-laden Ms than the respective IL-34-M subsets. This work marks the first report describing the roles of these M subsets in mycobacterial disease and may-well lead to the development of more targeted anti- Mtb approaches.