Mycobacterium tuberculosis extracellular vesicles induce the formation of granulomalike structures in an in vitro model

Abstract Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis. Only 10% of the infected individuals develop an active disease, while 90% of the infected individuals contain the mycobacteria inside structures known as granulomas, in a latent, asymptomatic state. The lung granuloma is formed by a core of infected macrophages, foam cells and epithelioid macrophages, surrounded by several lymphocyte subsets (CD4 T cells, CD8 T cells, Tγδ cells, NK cells, and B cells). M. tuberculosis releases extracellular vesicles, both spontaneously and under stress conditions; these vesicles carry components, derived from the mycobacterial cell wall, that are ligands for human Toll-like receptors (TLR) 2/6 and 4; as a result, these vesicles activate the innate immune system. To determine if M. tuberculosis extracellular vesicles induce the formation of a granuloma-like structure, we used an in vitro granuloma model, with peripheral blood mononuclear cells from individuals with latent TB (positive for the Quantiferon test). We found that M. tuberculosis extracellular vesicles induced the formation of granuloma-like structures that were similar in numbers, diameters and cellular composition (percentage of monocytes, T cells, Tγδ cells, NK cells and ILCs) to the granuloma-like structures formed in response to live M. tuberculosis H37Rv. These results suggest that M. tuberculosis extracellular vesicles participate in the cellular activation and migration processes that lead to granuloma formation in the lungs of TB patients. Supported by a grant 20190106 from Secretaría de Investigación y Posgrado, Instituto Politécnico Nacional.