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Cambridge researchers uncover how leprosy hijacks immune system


By Paul Brackley


Leprosy affected 176,176 people in 2015 according to the WHO
Leprosy affected 176,176 people in 2015 according to the WHO

Scientists at MRC Laboratory of Molecular Biology help to show how bacteria causes nerve damage.

Scientists in Cambridge have helped to uncover how leprosy hijacks our immune system, turning a mechanism for repair into one that causes irreparable damage to nerve cells.

Very little has been known about the biology of leprosy until now, but an international team of researchers were able to use genetically-modified zebrafish to study how the bacteria that causes it settled inside immune cells called macrophages that usually consume and destroy foreign bodies.

“These ‘Pac-Man’-like immune cells swallow the leprosy bacteria, but are not always able to destroy them,” said Professor Lalita Ramakrishnan, from the Department of Medicine at the University of Cambridge, whose lab is within the MRC Laboratory of Molecular Biology.

Nerve damage in leprosy is caused by the stripping away of the protective insulation, called the myelin sheath, that protects nerves fibres.

“The macrophages – which should be moving up and down the nerve fibre repairing damage – slow down and settle in place, destroying the myelin sheath,” said Prof Ramakrishnan.

Working with Dr Cressida Madigan, Prof Alvaro Sagasti and other colleagues, Prof Ramakrishnan confirmed that this was the case by knocking out the macrophages and showing that when the bacteria sit directly on the nerves, they do not damage the myelin sheath.

They also showed how a molecule known as PGL-1 reprograms the immune cell, causing it to overproduce nitric oxide, which damages the mitochondria, the ‘batteries’ that power nerves.

“The leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry,” said Prof Ramakrishnan. “It then starts spewing out toxic chemicals. Not only does it stop repairing damage, but it creates more damage itself.”

The findings, published in the journal Cell, appear to place leprosy in the same category of multiple sclerosis and Guillain–Barré syndrome.

The researchers say it is too early to say whether the work will lead to new treatments, although there are drugs being tested that inhibit the production of nitric oxide.

But Prof Ramakrishnan says the key may be to catch the disease at an early enough stage to prevent damage to the nerve cells.

“We need to be thinking about degeneration versus regeneration,” she says. “At the moment, leprosy can be treated by a combination of drugs. While these succeed in killing the bacteria, once the nerve damage has been done, it is currently irreversible. We would like to understand how to change that. In other words, are we able to prevent damage to nerve cells in the first place and can we additionally focus on repairing damaged nerve cells?”

The number of people with leprosy has declined massively. According to the World Health Organisation, if fell from 5.2 million people in 1985 to 176,176 at the end of 2015.

The Cambridge scientists worked with colleagues in Washington, Los Angeles and at Harvard.



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