title: Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis that survive antibiotic treatment.
abstract: During tuberculosis (TB), some Mycobacterium tuberculosis bacilli persist in the presence of an active immunity and antibiotics that are used to treat the disease. Herein, by using the Cornell model of TB persistence, we further explored our recent finding that suggested that M. tuberculosis can escape therapy by residing in the bone marrow (BM) mesenchymal stem cells. We initially showed that M. tuberculosis rapidly disseminates to the mouse BM after aerosol exposure and maintained a stable burden for at least 220 days. In contrast, in the lungs, the M. tuberculosis burden peaked at 28 days and subsequently declined approximately 10-fold. More important, treatment of the mice with the antibiotics rifampicin and isoniazid, as expected, resulted in effective clearance of M. tuberculosis from the lungs and spleen. In contrast, M. tuberculosis persisted, albeit at low numbers, in the BM of antibiotic-treated mice. Moreover, most viable M. tuberculosis was recovered from the bone marrow CD271(+)CD45(-)-enriched cell fraction, and only few viable bacteria could be isolated from the CD271(-)CD45(+) cell fraction. These results clearly show that BM mesenchymal stem cells provide an antibiotic-protective niche for M. tuberculosis and suggest that unraveling the mechanisms underlying this phenomenon will enhance our understanding of M. tuberculosis persistence in treated TB patients.
authors.affiliation: Department of Infectious Disease and Global Health, Tufts University Cummings School of Veterinary Medicine, Grafton, Massachusetts. Electronic address: gillian.beamer@tufts.edu.
authors.forename: Gillian
authors.initials: G
authors.lastname: Beamer
authors.affiliation: Department of Infectious Disease and Global Health, Tufts University Cummings School of Veterinary Medicine, Grafton, Massachusetts.
authors.forename: Samuel
authors.initials: S
authors.lastname: Major
authors.affiliation: Global Infectious Disease Research Center, The Forsyth Institute, Cambridge, Massachusetts; KaviKrishna Laboratory, Guwahati Biotech Park, Technology Complex, Indian Institute of Technology, Guwahati, India.
authors.forename: Bikul
authors.initials: B
authors.lastname: Das
authors.affiliation: Global Infectious Disease Research Center, The Forsyth Institute, Cambridge, Massachusetts. Electronic address: acampos@forsyth.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Campos-Neto
mesh_terms: D000068816:Adapalene; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000382:microbiology; D001854:Bone Marrow Cells / Q000382:microbiology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008168:Lung / Q000382:microbiology; D059630:Mesenchymal Stem Cells / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity*; D009281:Naphthalenes / Q000378:metabolism; D012293:Rifampin / Q000627:therapeutic use; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D009281:Naphthalenes; D000068816:Adapalene; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D007538:Isoniazid; D012293:Rifampin