Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence
Authors: Sujata Mohanty
Samreen Fatima
Gobardhan Das
Debapriya Bhattacharya
Santosh Kumar
Anand Ranganathan
Ved Prakash Dwivedi
Luc Van Kaer
Shashank Shivaji Kamble
Journal: Journal of Clinical Investigation (2020)
Discipline: CLINICAL MEDICINE
Keywords: Autophagy; Bacterial infections; Infectious disease; Stem cells; Tuberculosis.
Affiliations: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India., International Centre for Genetic Engineering and Biotechnology, New Delhi, India., Centre for Biotechnology, Siksha 'O' Anusandhan Deemed University, Bhubaneswar, India., Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA., All India Institute of Medical Sciences, New Delhi, India.

Abstract:  Tuberculosis (TB) remains a major infectious disease worldwide. TB treatment displays a biphasic bacterial clearance, in which the majority of bacteria clear within the first month of treatment, but residual bacteria remain nonresponsive to treatment and eventually may become resistant. Here, we have shown that Mycobacterium tuberculosis was taken up by mesenchymal stem cells (MSCs), where it established dormancy and became highly nonresponsive to isoniazid, a major constituent of directly observed treatment short course (DOTS). Dormant M. tuberculosis induced quiescence in MSCs and promoted their long-term survival. Unlike macrophages, where M. tuberculosis resides in early-phagosomal compartments, in MSCs the majority of bacilli were found in the cytosol, where they promoted rapid lipid synthesis, hiding within lipid droplets. Inhibition of lipid synthesis prevented dormancy and sensitized the organisms to isoniazid. Thus, we have established that M. tuberculosis gains dormancy in MSCs, which serve as a long-term natural reservoir of dormant M. tuberculosis. Interestingly, in the murine model of TB, induction of autophagy eliminated M. tuberculosis from MSCs, and consequently, the addition of rapamycin to an isoniazid treatment regimen successfully attained sterile clearance and prevented disease reactivation. 

Retracted: No

PubPeer comments:
 In Figure 1 I, several Westen blots are included. According to the Supplementary Figure 10, where the whole Western blots are presented, it looks like the authors have run all the Western blots separately, on different gels, which is highly questionable. Usually, when you want to study different proteins in an experiment, you cut the membrane into several pieces in order to stain with different antibodies. Surprisingly, this is apparently not done in this study. Furthermore, it is clear from the different MW markers that different gels have been used, which is not correct in order to compare the different proteins. ![file] , 
 #1  ...which is highly questionable 1. How should one compare three different forms of Foxo3a and two different forms of Foxo1 if not on separate gels? 2. If it s acceptable to compare proteins of the same or similar size on different gels, then why does it become highly questionable to do so with proteins of different sizes? , 
 #1 We thank you for showing interest in our paper. However, we would like to mention here that as per the journal guidelines to the authors, complete uncut gel pictures have to be produced for each protein. As per the journal policy, no cut is allowed, and therefore for each antibody, we have run a separate gel. Furthermore, most of the proteins detected have the same similar molecular weight and detection antibodies may have cross-reactivity. Nevertheless, it is nearly impossible to run 32 lanes with 8 different antibodies in one gel. Moreover, for better understanding and clarity of the readers, the original blot photographs have been provided in the supplementary information (also as per the journal guidelines). This figure has been prepared and provided totally as per journal requirements, which has been reviewed by reviewers, and editors. We hope that this answers your question. ,