Mycobacterium tuberculosis subverts the TLR-2-MyD88 pathway to facilitate its translocation into the cytosol.
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.
School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa ; Immunology Group, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
Aejazur
A
Rahman
Immunology Group, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
Parveen
P
Sobia
Immunology Group, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
Neeta
N
Gupta
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Luc Van
LV
Kaer
School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa.
Gobardhan
G
Das
D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004072:Digitonin; D017737:Macrophages, Peritoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009169:Mycobacterium tuberculosis / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013864:Thioglycolates; D051195:Toll-Like Receptor 2 / Q000378:metabolism
D017931:DNA Primers; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D013864:Thioglycolates; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D004072:Digitonin