Mesenchymal Stem Cells: A Hidden Arsenal for Mtb Persistence, Resuscitation, and Reactivation

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a global public health threat and remains the leading cause of death among infectious diseases. The pathogen has developed strategies to survive inside and outside diverse host cells under wide range of unfavorable conditions, leading to persistence, and also undergo reactivation in the event of favorable conditions. Several sources of endogenous reactivation are proposed, including specific host cells that could harbor viable and dormant Mtb in the protective intracellular compartments. However, it is not clear how these host cells could survive the hypoxic/oxidative stress microenvironment prevalent in the post-drug treated granulomas. Recently Das et al. identified human CD271+ bone marrow mesenchymal stem cells (CD271+ BM-MSCs) as niche host cells that can maintain viable, non-replicating dormant Mtb. Most importantly, from patients who had successfully completed anti-tubercular therapy, viable Mtb could be isolated from CD271+ BM-MSCs, and not in other types of cells including macrophages. The follow-up study showed that Mtb could escape anti-tubercular drug therapy by hiding intracellular to CD271+ BM-MSCs serving as source for endogenous reactivation of TB. With these studies at the forefront, a novel model of granuloma reactivation could be proposed where CD271+ BM-MSCs harboring viable Mtb migrate to inflammatory granulomas for disease reactivation. Moreover, CD271+BM-MSCs also are able to resuscitate the viable but non-culturable (VBNC) Mtb inside the granuloma to reactivate the disease. Studies show that pulmonary tuberculosis (PTB) patients with culture negative sputum contain an occult population of VBNC Mtb in their sputum. CD271+ host-Mtb interaction studies suggest that these VBNC may be resuscitate back to culturable state by CD271+MSCs. Study of mechanism of Mtb survival and resuscitation inside MSCs is challenging and ongoing. Hypoxia may play an important role in the survival and persistence of Mtb inside the MSCs in TB patients post therapy as well in mice drug-induced dormancy model indicated by upregulation of HIF-1alpha. Latent TB has been challenging and difficult to study because of the dynamic capability of Mtb to adapt easily for over 200 years in vivo and in vitro. Despite all the ongoing efforts, so far, targeting dormant TB seems difficult. Although there are drugs which target cell wall synthesis, transcription, translation, and ATPase activity in actively dividing stage, their efficacy against dormant bacilli is unclear. Isoniazid treatment for 9 months is recommended for latent or dormant TB; however, non-adherence to such long regimen is a problem; moreover in light of current studies the efficacy of isoniazid against dormant bacilli is questionable. Studies on Mtb residing inside MSCs may shed light into new therapeutics to target non-replicating bacteria as well as VBNC Mtb and prevent endogenous reactivation of the disease.