This article was published in Scientific American’s former blog network and reflects the views of the author, not necessarily those of Scientific American
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The bacteria that cause Tuberculosis are nasty little beasts. The white blood cells that clear infection in your body work by ingesting bacteria and then breaking them up, and the TB escapes this by letting itself get ingested and then sitting inside your white blood cells. They don't sit passively, however, they burst out of the cell and recruit a whole host of other blood cells which surround the infection and form what's called a granuloma. The bacteria stay inside the granuloma and become dormant, but if they escape they can set up other sites of infection throughout the body.
The white blood cells that first ingest the TB bacteria are macrophages, which kill invading particles (be they cells or bits of cells, or even dead parts of your own cells) by ingesting them into a vacuole and then breaking them down. The TB gets ingested fine, but once inside the cell, it stops the cell from breaking it down. That means that you now have a white blood cells infected with a TB bacterium.
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In order to create the granuloma, the TB bacterium needs to bring other white blood cells to the scene. The best way to do this is to rupture the cell that it's currently in, because bits of broken up cell are a great way to get the immune system rushing over. A recent paper in PloS (reference below) shows that in order to do this, the TB must break out of the vacuole holding it following ingestion, and then kill the host cell once it's in the cytoplasm:
This model is not a fully accepted one within the TB community, and there's still some conflict as to whether the bacterium actually breaks out of the vacuole it gets ingested into (as shown above) or whether it stays within the vacuole and wrecks havoc from there. The paper explores this using a technique called FRET. FRET works by using two fluorescent probes which, when they get close to each other, light up. If the two probes are far apart, no fluorescence is seen, but if they're in close proximity they light up like a fairy light and can be detected.
One half of the probe was attached to a protein found in the white blood cell cytoplasm, while the other was attached to a sugar found on the bacterial cell surface. What they found was not only does the bacterial sugar end up very close to the cytoplasmic protein, it does it relatively quickly. Within 24 h to 48 h after infection fluorescence could be detected in almost all the infected blood cells. A bit of tinkering around with knocking out bacterial protein activity also discovered a set of proteins that were vital for this process to occur: ESX-1.
ESX-1 gene codes for a secretion system, not surprising seeing as there job seems to be to get the bacteria out of the vacuole! Bacteria without the ESX-1 system stayed inside the vacuole for ten days and no FRET fluorescence was seen. Not only that, but it was only the cells with functional ESX-1 systems that were causing cell death. When the bacteria stayed in the vacuole (which is technically called a phagolysosome) the white blood cells remained alive, whereas once they managed to get out, the cells started dying. This seems to indicate that bacteria need to be in the cell cytoplasm before they can start killing off your cells and forming a granuloma.
The reference is open access so for more information, and for some great pictures of the FRET results, go take a look!
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Ref: Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, & Enninga J (2012). Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death. PLoS pathogens, 8 (2) PMID: 22319448
Credit for image 1.
Image 2 (c) me. Linkback if you want to borrow it.
