I read a really cool paper in Cell last week, about the bacterium that causes TB, Mycobacterium tuberculosis (M.tb.). This bacterium is unique for many reasons, but I’ll mention only one here. M.tb. is well known for its unusual ability to live a long and productive life inside the cells it infects, macrophages. Macrophages are important cells of the immune system, and are necessary for both the early innate immune response and the later adaptive immune response.
M.tb is really good at evading both these responses, and it does so partly because it manages to take up residence within a special sub-compartment of the cell, called the phagolysosome. One could think of these sub-compartments, or organelles, as rooms within the cell. The phagosome is like an entryway, where stuff goes when it is first swallowed up by the cell. The lysosome is the place where all material goes to be degraded and recycled back to use. The interior of a lysosome is very acidic, which promotes its function but makes it very difficult for proteins or bacteria to survive for long inside. The phagolysosome is a fusion of both, a special organelle that only forms in cells like macrophages and is a distinctly inhospitable place, but M.tb. manages to hang on pretty well.
The absolute dogma through many years of M.tb. research has been that the bacterium lives inside the phagolysosome and doesn’t come out. It is thought to cleverly subvert other intracellular transport and delivery systems to obtain its nutrients while never leaving its den. That M.tb. lives in this “privileged” niche is the reason that is commonly cited for its ability to evade recognition by the immune system. Specifically, one arm of the adaptive immune system, cytotoxic CD8 T cells. Briefly, CD8 T cells have T cell receptors that recognize small fragments of proteins, called peptides, carried on the cell surface by MHC class I proteins (MHC expands to major histocompatibility complex, the main determinants of transplant rejection, another time!). CD8 T cells kill the cells that “present” antigen to them in this fashion, and are, as you can imagine, very useful in protection against many a pathogen.
Here’s the catch, as far as M.tb. is concerned anyway. Peptides that are presented to CD8 T cells are generated by chopping up proteins in the cytosol, the living room of the cell. The chopped up pieces of proteins are then moved into the ER (endoplasmic reticulum, the kitchen-cum-pantry), where they undergo some fine-tuning and latch on to the MHC class I molecules that will take them to the surface. If M.tb. is as good at hiding in the phagolysosome as it seems and never comes out into the cytosol, it is hard to see how M.tb. proteins come into the orbit of MHC class I.
And many years of research have said just that: M.tb. stays in the phagolysosome and doesn’t enter the cytosol. Good research too, extensive, well done and detailed and using diverse approaches. However, Nicole van der Wel and her colleagues have refined their detection techniques (essentially sophisticated microscopy, electron and fluorescent) to the point where they see something different. They find that while M.tb. does enter the phagolysosome very shortly after infecting and entering the cell, 48 hours after infection it is out and about in the cytosol. Some of the bacterium does stay in the phagolysosome, but much of it escapes, and eventually causes the host cell to die. Also, they find that it is the disease causing Mycobacterium tuberculosis and Mycobacterium leprae (leprosy) that can escape into the cytosol while attenuated vaccine strains like Bacille Calmette-Guerin (BCG, do you have the scar to show for it?) cannot do so. To tie the whole thing up nicely, the authors find that certain bacterial genes are necessary for this property and when these genes are deleted form the bacterium, it cannot move into the cytosol and cannot kill the host cell anymore.
So, to summarize, van der Wel et al show that contrary to widely believed dogma, M.tb. can escape into the host cell cytosol. This means that the bacterium may not be as able to evade immunity as thought previously. Also, given that only disease-causing mycobacteria can do this and that BCG does not, it brings into question the relevance of BCG as a vaccine, or even a model for studying TB. It is now much easier to visualize how M.tb. provokes a CD8 T cell immune response now that it has been shown to enter the cytosol. This is a really essential point, as the immune response to M.tb. is what causes the infamous granulomas, or patches, that one sees on the X-rays. Finally the observation that M.tb. that invades into the cytosol more often than not ends up killing the host cell goes some way towards beginning to explain the mysterious latency of the bug. M.tb. is latent in more people than it manifests as a disease in, and often it needs some kind of trigger for a latent M.tb. infection to become full blown TB. Maybe its because the bacterium lives in uneasy equilibrium with its host, killing its hosts when it gets too invasive otherwise just existing, and only becomes really infective when an external event disturbs the equilibrium. Time will tell.
Fantastic paper, just fantastic.
M. tuberculosis and M. leprae Translocate from the Phagolysosome to the Cytosol in Myeloid Cells
Nicole van der Wel, David Hava, Diane Houben, Donna Fluitsma, Maaike van Zon, Jason Pierson, Michael Brenner and Peter J. Peters Cell 129 1287-1298.