Fresh clue to TB disease

How the tuberculosis bacterium overwhelms our immune defenses to trigger active TB disease has been demonstrated by scientists in South Africa.

Scientists estimate that up to one third of the world's population may be carrying TB, and at least two million people per year die of the diseae, which is caused by Mycobacterium tuberculosis bacteria.

The bug spreads when an infected person coughs out the organism and a susceptible individual breathes it in. The bacteria settle in the lung where they are sequestered by immune cells called macrophages.

Sometimes the bugs are held at bay, and the individual remains healthy, but at other times the infection accelerates and the patient is often overwhelmed and develops severe disease that can destroy the lungs and spread lethally to other tissues including bones, joints and even the brain and eyes.

This disease trajectory has been known for over a century, in fact since at least 1882 when Robert Koch famously announced to the world that he’d discovered the cause of the disease, but why the bacteria behave the way they do remained something of a mystery. 

Now Africa Health Research Institute scientist Alex Sigal, who's based in Durban, South Africa, has followed Robert Koch's example of painstaking observation and performed the world's first detailed time-lapse microscope study of how TB interacts with the immune cells it infects.

By taking images every ten minutes of the bacteria growing alongside cultured macrophages, he and his colleagues have discovered that how TB behaves depends upon the physical numbers of bacteria.

When small numbers of bacteria are present, the macrophages engulf them and imprison them within themselves, suppressing further growth of the bugs and preventing them from causing disease. But if the number of TB bacteria within a clump exceeds a critical threshold of about 50 bugs, their macrophage jailer is overwhelmed and dies.

Previously other observers had thought that the death of the macrophage would also lead to the demise of the TB bacteria it contained, but Sigal's microscope images tell a very different story.

"Actually the bacteria are very happy and they grow much faster inside the remains of the dead cell that they would otherwise, probably by scavenging the nutrients that have been released [when the cell died]," he explains. "But worse, the dead cell then becomes 'bait' to lure fresh macrophages, which move in to clean up the mess. They engulf the crowd of TB bacteria and are themselves then killed, further amplifying the numbers of bacteria and the pace of the disease."

"It becomes a vicious cycle," says Sigal.

At the moment, the team don't know what triggers the TB bacteria to increase in number, triggering the process in the first place. "Perhaps there is a loss of immune control," Sigal speculates. "That's what we are trying to uncover now."

They also acknowledge that their experiments, published in the journal eLife and using TB bacteria that make a fluorescent red marker to make them easy to follow with a microscope, were conducted in a culture dish and therefore cannot reproduce the full spectrum of the immune response. Nevertheless, it's very likely that the observations are highly relevant to the real clinical disease process and perhaps explain the abrupt acceleration in disease progression characteristically seen in some patients.