3 years ago

Mice bone marrow Sca-1(+)/CD44(+)mesenchymal stem cells kill avirulent mycobacteria but not Mycobacterium tuberculosis through modulation of cathelicidin expression via p38 MAPK dependent pathway.

Sonawane A, Naik SK, Ganguli G, Das D, Pati S, Sengupta S, Padhi A
Mycobacterium tuberculosis (Mtb) primarily infects lung macrophages. However, recent study has shown that Mtb also infect and persist in dormant form inside the bone marrow mesenchymal stem cells (BM-MSCs) even after successful antibiotic therapy. However, the mechanism(s) by which Mtb survives 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-1+/CD44+ BM-MSCs. We found that BM-MSCs were able to kill avirulent Mycobacterium smegmatis and M. bovis-BCG, but not the pathogenic Mtb Further mechanistic studies revealed that pathogenic Mtb dampen the antibacterial response of BM-MSCs by down-regulating the expression of cationic antimicrobial peptide cathelicidin. In contrast, avirulent mycobacteria were effectively killed by inducing TLR2/4 pathway dependent expression of cathelicidin, while siRNA mediated cathelicidin silencing increased the survival of M.bovis-BCG in BM-MSCs. We also showed that M. bovis-BCG infection caused increase in the expression of MyD88, phospho- IRAK-4 and p38 MAPK signaling pathway. Further downstream investigation demonstrated that IRAK-4/p38 activation increased the nuclear translocation of NF-κB that subsequently induced the expression of cathelicidin and IL-1β cytokine resulting in decreased survival of M. bovis-BCG. On the other hand inhibition of TLR2/4, pIRAK-4, p38 and NF-κB nuclear translocation decreased cathelicidin and IL-1β expression and therefore increased the survival of avirulent mycobacteria. This is the first report which demonstrates that virulent mycobacteria manipulate TLR2/4/MyD88/IRAK4/p38/NF-κB/Camp/IL-1β pathway to survive inside bone marrow stem cells.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28739828

DOI: PubMed:28739828

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