When the bacteria that causes tuberculosis invades the human body, a drama unfolds at the cellular level involving invasions, toxic poisons, shape-shifting, prisons and daring escape plans. Now researchers at the Francis Crick Institute have watched it all play out in real time. The finding could help the battle against bacteria that have become resistant to traditional treatments.

After the TB-causing bacteria known as Mycobacterium tuberculosis enter the body, they are engulfed in immune system cells known as macrophages. Inside these cells are further containers known as phagosomes. The phagosomes act as a kind of holding cell for the bacteria, keeping it prisoner until toxic enzymes and chemicals can arrive on site to kill it. The problem is that M. tuberculosis doesn't wait patiently by. It can escape from the phagosomes by poking holes in its membrane. It can then leak into the cell, kill it, and feed on its carcass.

However, by lighting up the phagosomes with fluorescent markers and then watching them handle an invasion of M. tuberculosis under the microscope, researchers at the Francis Crick Institute in London were able to discover a trick the phagosomes use to outsmart the bug. The release of a protein known as Rab20 causes the phagosomes to grow in size, thwarting the bacteria's efforts to reach and pierce their membranes. This causes the invaders to remain trapped inside until the bacteria-blasting chemicals can arrive and eliminate them.

"We have known for a while that tight and spacious phagosomes exist, but it is only now becoming clear why there are two types," says Laura Schnettger, the first author of the paper and former PhD student at Crick.

The nuclei of the macrophages are shown blue, while the phagosomes, which corral bacterial invaders, are shown in red(Credit: Laura Schnettger, Francis Crick Institute)

"If you think of a cell as a city with lots of different types of transport then Rab proteins are the master regulators of public transport," added Maximiliano Gutierrez, group leader at the Francis Crick Institute, who led the study. "They tell components in a cell where to go. Rab20 directs more membrane to the phagosome, enlarging it and preventing the bacteria from getting out."

The researchers also found more Rab20 in the phlegm coughed up by TB patients than in those without the infections, which helps support the chemical's role in combating the disease. The researchers hope that both findings could help them develop strategies to assist the phagosomes in enlarging and thwarting even antibiotic-resistant strains of TB.

"The capture and escape of M. tuberculosis in cells is a highly dynamic process, so the only way you can understand what is going on is to image cells in real time at very high resolution," said Maximiliano." We are one of the few labs in the world that can perform long-term live cell imaging at sub-cellular resolution with the safety infrastructure required to work with a life-threatening bacterium."

The results of the study have been published in the journal Cell Host & Microbe.

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