title: Preclinical and Clinical Evidence of Mycobacterium tuberculosis Persistence in the Hypoxic Niche of Bone Marrow Mesenchymal Stem Cells after Therapy.
abstract: Mycobacterium tuberculosis (MTB), the causative agent of pulmonary tuberculosis, is difficult to eliminate by antibiotic therapy. We recently identified CD271(+) bone marrow-mesenchymal stem cells (BM-MSCs) as a potential site of MTB persistence after therapy. Herein, we have characterized the potential hypoxic localization of the post-therapy MTB-infected CD271(+) BM-MSCs in both mice and human subjects. We first demonstrate that in a Cornell model of MTB persistence in mice, green fluorescent protein-labeled virulent MTB-strain H37Rv was localized to pimonidazole (an in vivo hypoxia marker) positive CD271(+) BM-MSCs after 90 days of isoniazid and pyrazinamide therapy that rendered animal's lung noninfectious. The recovered CD271(+) BM-MSCs from post-therapy mice, when injected into healthy mice, caused active tuberculosis infection in the animal's lung. Moreover, MTB infection significantly increased the hypoxic phenotype of CD271(+) BM-MSCs. Next, in human subjects, previously treated for pulmonary tuberculosis, the MTB-containing CD271(+) BM-MSCs exhibited high expression of hypoxia-inducible factor 1α and low expression of CD146, a hypoxia down-regulated cell surface marker of human BM-MSCs. These data collectively demonstrate the potential localization of MTB harboring CD271(+) BM-MSCs in the hypoxic niche, a critical microenvironmental factor that is well known to induce the MTB dormancy phenotype.
authors.affiliation: KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India; Molecular Biology and Genetic Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Jaishree
authors.initials: J
authors.lastname: Garhyan
authors.affiliation: KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Bhuyan
authors.affiliation: KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India.
authors.forename: Ista
authors.initials: I
authors.lastname: Pulu
authors.affiliation: KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India.
authors.forename: Deepjyoti
authors.initials: D
authors.lastname: Kalita
authors.affiliation: KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India; Department of Immunity and Infectious Diseases, Forsyth Institute, Cambridge, Massachusetts. Electronic address: bdas@forsyth.org.
authors.forename: Bikul
authors.initials: B
authors.lastname: Das
authors.affiliation: Molecular Biology and Genetic Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India. Electronic address: rakeshbhatnagar@jnu.ac.in.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhatnagar
mesh_terms: D000068816:Adapalene / Q000276:immunology*; D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology*; D015687:Cell Hypoxia; D015536:Down-Regulation; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity / Q000502:physiology*; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D013047:Specific Pathogen-Free Organisms; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D049452:Green Fluorescent Proteins; D000068816:Adapalene; C033815:pimonidazole; D007538:Isoniazid