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.

Human and Mouse Hematopoietic Stem Cells Are a Depot for Dormant Mycobacterium tuberculosis

“…Thereby, we detected between one and ten copies of Mtb -specific DNA within lysates of 10 3 MSCs by real-time TaqMan PCR targeting MPB64 and IS6110 from blood of human donors with LTBI (Fig 1A), in confirmation of previous results by Das et al . [23, 24]…”

“…Das et al . have reported that human bone marrow CD271 + CD45 − MSCs in vitro as well as an equivalent population of bone marrow MSCs in the mouse may provide a long-term protective intracellular niche in the host in which Mtb can reside [23, 24]. The quiescence of the hypoxic niche of mesenchymal and hematopoietic cells could provide stress and induce dormancy genes of Mtb [25–27].…”

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

“…43 The consequences of this specialized milieu are evident clinically in the frequent occurrence of tumour metastases in bone (see later), as well as serious infections such as tuberculosis involving this tissue prior to widespread dissemination. 44 …”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…Jaishree Garhyan (Jawaharlal Nehru University, India) reported bone marrow to be a niche for persisters as the mesenchymal stem cells survive for an extended period of time and reside in immune suppressed environments. 51,52 Additionally, stem cells have active drug efflux cells providing a second wall of defense for the pathogen. Their work indicates that M. tuberculosis hijack mesenchymal stem cells, reprogramme them through hypoxia inducible factor (Hif-1) and targeting this pathway could potentiate standard treatment regimens.…”