The New Paradigm of Immunity to Tuberculosis by Maziar Divangahi

Author:Maziar Divangahi
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

Short of bacterial translocation, there is increasing evidence that M. tuberculosis has the capacity to damage host cells membranes and it is likely that this includes damage to the phagosomal membrane. Damage of the phagosomal membrane would allow bacterial products to leak out of the phagosome and into the cytosol. Alternately, active transport by a secreted bacterial transport apparatus (similar to the ESX-1 type VII secretion system) could translocate bacterial proteins across the phagosomal membrane. Both of these scenarios would introduce mycobacterial antigens into the cytosol of the infected cell where they could be sampled by the class I MHC processing pathway.

Finally, the finding that uninfected DC that take up apoptotic infected cells cross-present mycobacterial antigens, leading to cross-priming of CD8+ T cells, indicates that phagosomal antigens in DC have the capacity to enter the class I MHC processing pathway whether or not there are viable bacteria present [28, 67–70]. The bias towards presentation of secreted proteins could arise if soluble proteins are preferentially packaged into apoptotic blebs. How the antigens get out of the apoptotic vesicles, which are taken up by efferocytosis, and into the cytosol, still remains a formidable problem to solve. There must be host mechanisms that facilitate sampling of antigens from endocytic compartments. One possible mechanism involves the host protein Sec61, which normally mediates retrograde protein translocation as a way to transport misfolded proteins back into the cytosol where they can be targeted for degradation. Proteins secreted by M. tuberculosis into the phagosomal compartment might be translocated by Sec61 across the phagosomal membrane into the cytosol where they could enter the class I MHC processing pathway [78].

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