The bug, having existed in the world far longer than us, springs some evolutionary survival tricks

What a tangled web we weave

When first we practice to deceive

Sir Walter Scott (1771-1832)

Tuberculosis or TB is an ancient disease that has affected humankind since historical times.

Analysis of some of the mummies of Egyptian royalty has suggested that they suffered from TB. Until recent times, no cure was known for TB; antibiotics are less than a century-old invention. The bodies of affected individuals were slowly deprived of all energy.

No definitive cure

Since no definitive cure was known, patients were housed in sanatoria where the air was clear and healthy, in order to try and recuperate.

Two of these sanatoria were in Tambaram near Chennai and Horseley Hills off Madanapalle. Yet, many of them died a slow death due to “consumption,” as TB was known then. Our body fights infections of this kind from pathogens, using an army of cells. Some of them produce molecules that attack the pathogen; some others simply try and gobble it up. And once the body recognizes the pathogen, it remembers and generates immunity against future infection by the same pathogen.

But for this protective armour of immunity, we will all have gone long ago. Once bitten, twice prepared.

TB is a widespread disease, killing millions worldwide every year. The TB bacterium is all around us, and makes its living by eating us. But not always.

Thanks to our immune system, we know how to capture it and keep it imprisoned, even if we cannot kill it off completely or rid it from our system.

A whole slew of cells called macrophages and lymphocytes surround the bacteria (that still manage to survive) and form a sphere of tightly bound cells, and these balls are called granulomas.

Granulomas are thus a half-way defence system. They reflect the inability of the immune system to totally eradicate the pathogen. Most of us are actually chronically infected by TB. But there are no symptoms or illness.

However, this stalemate is broken when some unfortunate trigger releases the quarantined bug. The infection then flares up to become illness, and can be transmitted to others.

“Checkmate” situation

It is this “checkmate” situation that we must try and understand, so that the body can be rid of the bad bugs. And the bug, having been around in the world far longer than we have been, has some evolutionary survival tricks up its sleeve. It is a matter of who blinks first.

An insight into how the TB bacterium (called MTB) manages to survive within the strong fortress of the granuloma has come recently. How does it suppress the immune action of the surrounding cells? The answer, given by Dr. Gobardhan Das and colleagues from Delhi, is a big surprise. These researchers find that MTB recruits, of all things, stem cells from the infected body, and uses it as a shield or the “Kavacha Kundala” of the type that Karna in the Mahabharata had.

Dr. Gobardhan Das is an immunologist, who trained earlier at IMTECH Chandigarh and Yale in the US before joining the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Delhi.

Here, he was encouraged to work in the group on TB. The results of this work appear in the December 7, 2010 issue of PNAS.

The group first looked at the differences in the way the immunity-providing T cells of healthy and TB-infected mice behave.

The latter divide (actually multiply) far slower than the former. And they found the reason was that the tissue of the infected mice (from where they got the T cells) contained another cell type, while the healthy ones did not. And the mystery cells were actually one type (termed mesenchymal) of stem cells coming from the bone marrow of the mouse!

Huge surprise

This was huge surprise. We know stem cells are helpful ones that divide and produce many other cells types that go to make tissues and organs of the body. What are they doing near the infection?

Now, Das and group turned from mouse to man (actually five women) and studied the granulomas of these patients. Here again they found the presence of mesenchymal stem cells, and these were located between the infecting TB bacterial cells and the body's T cells of the granuloma.

Protective armour

Here then is the protective armour of the pathogen. The wily bug recruits an important family of cells from the body as its hostage for survival. Sir Walter Scott's words above appear to ring true for MTB.

What role is the stem cell playing there? The group shows that as it is sandwiched between the bug and the T cells, it produces a burst of molecular fireworks, in the form of the gas nitric oxide (formula NO), and the molecule called TGF-beta.

The former cuts down the number of bug cells and T-cells, the latter inhibits the action of T cells.

Surprising role

It would thus seem that the stem cells act as the UN peace keeping forces, keeping both adversaries in check. Here then is another, surprising role, for stem cells.

The ICGEB group ends their paper in PNAS stating that these findings identify mesenchymal stem cells as potential targets for therapeutic intervention in tuberculosis.

But I worry about what side effects might arise when one does this. Recall that the word stem has multiple meanings. As you stem the activity of a stem cell, will you not stem its stemness too? Is that good?

D. BALASUBRAMANIAN

dbala@lvpei.org

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