Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence.

Area of Science:

• Infectious Diseases
• Cell Biology
• Microbiology

Background:

• Tuberculosis (TB) is a global health challenge with treatment difficulties due to persistent, drug-resistant bacteria.
• Standard TB treatment (DOTS) involves isoniazid, but residual bacteria can develop resistance.
• Mycobacterium tuberculosis (M.tb) persistence is a key factor in TB treatment failure and relapse.

Purpose of the Study:

• To investigate the role of mesenchymal stem cells (MSCs) in Mycobacterium tuberculosis (M.tb) dormancy and treatment resistance.
• To elucidate the mechanisms by which M.tb establishes dormancy within MSCs.
• To explore novel therapeutic strategies targeting M.tb reservoirs in MSCs.

Main Methods:

• Co-culture of M.tb with human MSCs to observe bacterial uptake and intracellular localization.
• Analysis of M.tb dormancy markers and response to isoniazid within MSCs.
• Investigation of M.tb-induced changes in MSCs, including quiescence and lipid metabolism.
• Murine model of TB treated with isoniazid and rapamycin (autophagy inducer).

Main Results:

• M.tb was taken up by MSCs, establishing dormancy and becoming highly resistant to isoniazid.
• Dormant M.tb induced MSC quiescence and promoted their survival.
• Unlike macrophages, M.tb resided in the cytosol of MSCs, utilizing host lipid synthesis for survival within lipid droplets.
• Inhibition of lipid synthesis sensitized M.tb to isoniazid.
• In a murine TB model, autophagy induction eliminated M.tb from MSCs, and combining rapamycin with isoniazid achieved sterile clearance and prevented relapse.

Conclusions:

• MSCs act as a natural reservoir for dormant M.tb, contributing to treatment non-responsiveness and potential resistance.
• M.tb dormancy within MSCs is linked to host lipid synthesis and intracellular location.
• Targeting M.tb reservoirs in MSCs, particularly through autophagy induction, offers a promising strategy for achieving complete TB eradication.