Abstract
Mycobacterium tuberculosis (M.tb) has evolved mechanisms to evade its destruction in phagolysosomes, where it successfully survives and replicates within phagocytes. Recent studies have shown that virulent strains of M.tb can translocate from the phagosome into the cytosol of dendritic cells (DC). The molecular mechanisms by which virulent M.tb strains can escape the phagosome remain unknown. Here we show that the virulent M.tb strain H37Rv, but not the vaccine strain Bacille Calmette-Guérin (BCG), escapes from the phagolysosome and enters the cytosol by interfering with the TLR-2-MyD88 signaling pathway. Using H37Rv mutants, we further demonstrate that the region of difference-1 (RD-1) locus and ESAT-6, a gene within the RD-1 locus, play an important role in the capacity of M.tb to migrate from the phagosome to the cytosol of macrophages. H37Rv, BCG, H37RvΔRD1, and H37RvΔESAT6 were able to translocate to the cytosol in macrophages derived from TLR-2- and MyD88-deficient animals, whereas only virulent H37Rv was able to enter the cytosol in macrophages from wild type mice. Therefore, signaling through the TLR-2–MyD88 pathway in macrophages plays an important role in confining M.tb within phagolysomes. Virulent strains of M.tb have evolved mechanisms to subvert this pathway, thus facilitating their translocation to the cytosol and to escape the toxic microenvironment of the phagosome or phagolysosome.
Highlights
Phagocytes, the primary innate immune cells, engulf microorganisms in phagosomes, which later fuse with lysosomes
We further found that ESAT-6 (DESAT-6) and region of difference 1 (RD-1) (DRD-1) mutants of H37Rv were unable to translocate to the cytosol, suggesting that the ESAT-6/CFP-10 complex plays an important role in the escape of virulent M.tb from the phagolysosome to the cytosol
We treated these digitonin permeabilized infected macrophage with 0.2% tritonX-100, and we found that both H37Rv and Bacille CalmetteGuerin (BCG) were stained with M.tb specific antibody
Summary
Phagocytes, the primary innate immune cells, engulf microorganisms in phagosomes, which later fuse with lysosomes. Recent studies have demonstrated that M.tb and M. leprae successfully translocate to the cytosol from the phagolysosome in dendritic cells (DCs) [5]. The ESAT-6/CFP10 complex has been shown to play an important role in release and spread of M.tb to neighbouring cells [10] but the mechanism employed by M.tb to translocate from the phagolysosome to the cytosol remains elusive [11]. Previous studies have indicated that the Toll-like receptor (TLR) pathway plays an important role in phagosome maturation or phagolysosome formation [12]. We examined if TLR signaling has a role in intracellular translocation of M.tb from phagolysosomes to the cytosol in macrophages
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