In late stage infection TB becomes a cell ‘serial killer’ [with video]

Using time-lapse microscopy, researchers from the laboratory of Alex Sigal at the Africa Health Research Institute (AHRI) and Max Planck Institute for Infection Biology have discovered the mechanism that Mycobacterium tuberculosis (Mtb) uses to break down host defences in late stage infection.

HFSP Career Development Award holder Alex Sigal and colleagues
authored on Fri, 17 February 2017

In a paper published in eLife, researchers show for the first time how Mtb turns lung granulomas, usually tasked with controlling TB infection, against the body.

Mtb is the mycobacterium which causes tuberculosis (TB). Globally there are an estimated 10 million new cases of TB diagnosed each year and it is the cause of about 2 million deaths. TB is one of the leading causes of death in 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 Mtb and dead and decaying material from macrophages, is coughed up out of the lung. This allows Mtb 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 Sigal lab observed that Mtb bacteria clump together, ‘ganging up’ on one macrophage. They are not killed when they kill the macrophage. Instead, they 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. Mtb therefore uses macrophages as both fuel to grow on, and bait to attract the next cell.

“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 Sigal.

Video: 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.

Reference

Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells. Mahamed, D., Boulle, M., Ganga, Y., Mc Arthur, C., Skroch, S., Oom, L., Catinas, O., Pillay, K., Naicker, M., Rampersad, S., Mathonsi, C., Hunter, J., Sreejit, G., Pym, A. S., Lustig, G., & Sigal, A. (2017). eLife, 6, e22028. doi: 10.7554/eLife.22028.

Pubmed link