Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 185, Issue 7, Pages 1924-1934Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.03.028
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- Research Institute of World's Ancient Traditions, Cultures and Heritage (Roing, Arunachal Pradesh, India)
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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 1 alpha 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.
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