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Anti-tuberculosis (TB) drugs, while being highly potent in vitro, require prolonged treatment to control  Mycobacterium tuberculosis  ( Mtb ) infections in vivo. We report here that mesenchymal stem cells (MSCs) shelter  Mtb  to help tolerate anti-TB drugs. MSCs readily take up  Mtb  and allow unabated mycobacterial growth despite having a functional innate pathway of phagosome maturation. Unlike macrophage-resident ones, MSC-resident  Mtb  tolerates anti-TB drugs remarkably well, a phenomenon requiring proteins ABCC1, ABCG2 and vacuolar-type H + ATPases. Additionally, the classic pro-inflammatory cytokines IFNγ and TNFα aid mycobacterial growth within MSCs. Mechanistically, evading drugs and inflammatory cytokines by MSC-resident  Mtb  is dependent on elevated PGE2 signaling, which we verify in vivo analyzing sorted CD45 − Sca1 + CD73 + -MSCs from lungs of infected mice. Moreover, MSCs are observed in and around human tuberculosis granulomas, harboring  Mtb  bacilli. We therefore propose, targeting the unique immune-privileged niche, provided by MSCs to  Mtb , can have a major impact on tuberculosis prevention and cure.

Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis