Background: Several Mycobacterium tuberculosis glycoproteins are involved in tuberculosis pathogenesis. Results: Mycobacterium tuberculosis Rv3242c and Mycobacterium marinum mimG enhance bacillary survival by inhibiting oxidative stress and autophagy pathways in macrophages and zebrafish. Conclusion: Rv3242c and mimG aid intracellular bacterial persistence by modulating host immune responses. Significance: This study has identified a novel virulence factor, which can be considered as drug target for tuberculosis treatment.

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Host redox dependent physiological responses play crucial roles in the determination of mycobacterial infection process. Mtb explores oxygen rich lung microenvironments to initiate infection process, however, later on the bacilli adapt to oxygen depleted conditions and become non-replicative and unresponsive toward anti-TB drugs to enter in the latency stage. Mtb is equipped with various sensory mechanisms and a battery of pro- and anti-oxidant enzymes to protect themselves from the host oxidative stress mechanisms. After host cell invasion, mycobacteria induces the expression of NADPH oxidase 2 (NOX2) to generate superoxide radicals ( ), which are then converted to more toxic hydrogen peroxide (H 2 O 2 ) by superoxide dismutase (SOD) and subsequently reduced to water by catalase. However, the metabolic cascades and their key regulators associated with cellular redox homeostasis are poorly understood. Phagocytosed mycobacteria en route through different subcellular organelles, where the local environment generated during infection determines the outcome of disease. For a long time, mitochondria were considered as the key player in the redox regulation, however, accumulating evidences report vital role for peroxisomes in the maintenance of cellular redox equilibrium in eukaryotic cells. Deletion of peroxisome-associated peroxin genes impaired detoxification of reactive oxygen species and peroxisome turnover post-infection, thereby leading to altered synthesis of transcription factors, various cell-signaling cascades in favor of the bacilli. This review focuses on how mycobacteria would utilize host peroxisomes to alter redox balance and metabolic regulatory mechanisms to support infection process. Here, we discuss implications of peroxisome biogenesis in the modulation of host responses against mycobacterial infection.

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Mycobacterium tuberculosis primarily infects lung macrophages. However, a recent study showed that M. tuberculosis also 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 which M. tuberculosis 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 ϩ CD44 ϩ BM-MSCs. We found that BM-MSCs were able to kill avirulent Mycobacterium smegmatis and Mycobacterium bovis BCG but not the pathogenic species M. tuberculosis. Further mechanistic studies revealed that pathogenic M. tuberculosis dampens 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 of M. bovis BCG in BMMSCs. We also showed that M. bovis BCG 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-B, which subsequently induced the expression of cathelicidin and the cytokine interleukin-1␤ (IL-1␤), resulting in the decreased survival of M. bovis BCG. On the other hand, inhibition of TLR2/4, pIRAK-4, p38, and NF-B nuclear translocation decreased cathelicidin and IL-1␤ 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-B-Camp-IL-1␤ pathway to survive inside bone marrow stem cells.