Interactions of Mycobacterium tuberculosis with Human Mesenchymal Stem Cells

Tuberculosis is a leading cause of death due to infections in mankind. The causative pathogen Mycobacterium tuberculosis (Mtb) infects macrophages but also many other mammalian cells including hematopoietic and mesenchymal stem cells (MSCs). MSCs are multipotent and can differentiate into multiple cell phenotypes including macrophage like cells that express scavenger receptor-A (SR-A), mannose receptor, TLR-2/4 and contain NOD1/2 receptors in the cytosol. They express very low levels of HLA-DR (MHC-II) and HLA-ABC (MHC-I) because of which, they can be transplanted without adverse reactions. MSCs have self-renewal and regenerative properties, and secrete cytokines and chemokines; growth factors to reduce inflammation, repair and remodel tissues and maintain homeostasis. Thus, they have been used to treat human diseases including tuberculosis. Mtb infects MSCs from both humans and mice and persists within them for prolonged periods. We illustrate here that naive MSCs interact with Mtb by phagocytosing them through SR-A, and killing them through intrinsic autophagy and nitric oxide. Persisting organisms then become dormant, and thus MSCs provide a niche for latent tuberculosis. Naive MSCs usually exert immunosuppressive properties on macrophages, T cells and DCs although they can be immune-enhancing depending on environmental milieu, and prior activation with cytokines like IFN-γ. Therefore, MSCs can play a dual role during the pathogenesis of tuberculosis. First, MSCs internalize Mtb either during primary aerosol infection or during progressive disease and migrate to bone marrow, where, they provide a niche, and secrete cytokines to dampen immune cell function. Secondly, they can kill replicating Mtb through autophagy and NO but seem to require additional activation or drugs for complete elimination of dormant Mtb. Since MSCs can be grown in vitro into large numbers for transplantation, and can be either pharmacologically or genetically modified, we discuss emerging stem cell based immunotherapeutic strategies for tuberculosis.