Inhibition of ABCG2 efflux pumps renders the Mycobacterium tuberculosis hiding in mesenchymal stem cells responsive to antibiotic treatment

摘要

The lengthy TB chemotherapeutic regimen, resulting in the emergence of drug resistance strains, poses a serious problem in the cure of the disease. Further, one-quarter of the world's population is infected with dormant M.tb, which creates a lifetime risk of reactivation. M.tb has a remarkable tendency to escape the host immune responses by hiding in unconventional niches. Recent studies have shown that bone-marrow mesenchymal stem cells (BM-MSCs) can serve as a reservoir of the pathogen and have been suggested to keep them beyond the reach of anti-TB drugs. In this study, we have shown that M.tb infects and grows inside BM-MSCs and were unresponsive to the anti-TB drugs rifampicin and isoniazid when compared to the pathogen residing inside THP-1 macrophages. It was further shown that the ABCG2 efflux pumps of the BM-MSCs were upregulated upon exposure to rifampicin, which may be the contributing factor for the antibiotic unresponsiveness of the bacteria inside these cells. Subsequently, it was shown that inhibition of ABCG2 efflux pumps along with administration of anti-TB drugs led to an increased susceptibility and consequently an enhanced killing of the M.tb inside BMMSCs. These findings for the first time show that the MIC99 values of anti-TB drugs increase many folds for the M. tb residing in BM-MSCs as compared to M.tb residing inside macrophages and the involvement of ABCG2 efflux pumps in this phenomenon. Our study substantiates that these BM-MSCs acts as a useful niche for M.tb wherein they can survive by escaping the antibiotic assault that can be attributed to the host ABCG2 efflux pumps. Inhibiting these efflux pumps can be an attractive adjunctive chemotherapy to eliminate the bacteria from this protective niche.