In late stage infection TB becomes a macrophage ‘serial killer’
Using cutting edge technologies, Africa Health Research Institute (AHRI) scientists have discovered the mechanism which Mycobacterium tuberculosis (M.tb) uses to break down host defences in late stage infection.
In a paper published in eLife, researchers for the first time show how M.tb turns lung granulomas, usually tasked with controlling TB infection, against the body.
Mycobacterium tuberculosis (M.tb) is the bacteria that causes tuberculosis (TB). Globally there are an estimated 10-million new cases of TB diagnosed each year and it is responsible for close to 2-million deaths. TB is one of the leading causes of death in South Africa.
In a TB-infected person the immune system tries to control and isolate infection by forming protective ‘nodules’ in the lung called granulomas. Granulomas are made up of a core of macrophages, a type of white blood cell that fights disease by engulfing pathogens and keeping them in a cellular compartment where they are killed or cannot grow. However, when macrophages inside the granuloma die off in large numbers they lose control and the granuloma, now a combination of live M.tb and dead and decaying material from macrophages, is coughed up out of the lung. This allows M.tb to be transmitted to other people.
The processes involved in tipping the granuloma from a structure which effectively isolates and controls the infection to a structure which promotes it were previously not understood.
Using long duration time-lapse microscopy to image TB infection dynamics in human macrophages, researchers in the lab of Dr Alex Sigal set out to find answers.
They show how M.tb bacilli clump, ‘ganging up’ on one macrophage. They are not killed when they kill the macrophage and instead rapidly grow inside the dead cell, with a doubling time faster than the extracellular environment and in live cells. The next macrophage to pick up the dead infected cell will have more bacteria to deal with, and so a higher chance of dying. “M.tb therefore uses macrophages as both fuel to grow on, and bait to attract the next cell,” said Dr Sigal.
“In this study, we show that once a cascade of cellular infection starts with a clump of TB, it is very difficult to stop. An important next step would be to understand, at the cellular level, how that initial clump of bacteria was allowed to form,” said Dr Deeqa Mahamed, lead author on the paper.
Above: How M.tb ‘serially kills’ macrophages: Outlined cells are those which will be killed by a clump of TB. Serial killing order is: Green – Yellow – Magenta – Blue, with the serial killing TB clump moving top right to bottom left. What enables the serial killing is 1) The TB bacteria clump together, enabling them to gang up on one macrophage. 2) They are not killed when they kill the macrophage. 3) They rapidly grow inside the dead macrophage so that the next cell to pick up the dead infected cell will have more bacteria to deal with, and so a higher chance of dying.
Read the full paper here.