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

Neharika Jain, Haroon Kalam, Lakshyaveer Singh, Vartika Sharma, Saurabh Kedia, Prasenjit Das, Vineet Ahuja and Dhiraj Kumar ()
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Neharika Jain: International Centre for Genetic Engineering and Biotechnology
Haroon Kalam: International Centre for Genetic Engineering and Biotechnology
Lakshyaveer Singh: International Centre for Genetic Engineering and Biotechnology
Vartika Sharma: International Centre for Genetic Engineering and Biotechnology
Saurabh Kedia: All India Institute of Medical Sciences
Prasenjit Das: All India Institute of Medical Sciences
Vineet Ahuja: All India Institute of Medical Sciences
Dhiraj Kumar: International Centre for Genetic Engineering and Biotechnology

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16877-3

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