Mouse Bone Marrow Sca-1CD44Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway.

primarily infects lung macrophages. However, a recent study showed thatalso infects and persists in a dormant form inside bone marrow mesenchymal stem cells (BM-MSCs) even after successful antibiotic therapy. However, the mechanism(s) by whichsurvives in BM-MSCs is still not known. Like macrophages, BM-MSCs do not contain a well-defined endocytic pathway, which is known to play a central role in the clearance of internalized mycobacteria. Here, we studied the fate of virulent and avirulent mycobacteria in Sca-1CD44BM-MSCs. We found that BM-MSCs were able to kill avirulentandBCG but not the pathogenic speciesFurther mechanistic studies revealed that pathogenicdampens the antibacterial response of BM-MSCs by downregulating the expression of the cationic antimicrobial peptide cathelicidin. In contrast, avirulent mycobacteria were effectively killed by inducing the Toll-like receptor 2/4 (TLR2/4) pathway-dependent expression of cathelicidin, while small interfering RNA (siRNA)-mediated cathelicidin silencing increased the survival ofBCG in BM-MSCs. We also showed thatBCG infection caused increased expression levels of MyD88, phospho-interleukin-1 receptor-associated kinase 4 (pIRAK-4), and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Further downstream investigations demonstrated that IRAK-4-p38 activation increased the nuclear translocation of NF-κB, which subsequently induced the expression of cathelicidin and the cytokine interleukin-1β (IL-1β), resulting in the decreased survival ofBCG. On the other hand, inhibition of TLR2/4, pIRAK-4, p38, and NF-κB nuclear translocation decreased cathelicidin and IL-1β expression levels and therefore increased the survival of avirulent mycobacteria. This is the first report that demonstrates that virulent mycobacteria manipulate the TLR2/4-MyD88-IRAK-4-p38-NF-κB-Camp-IL-1β pathway to survive inside bone marrow stem cells.