The bacteria that cause leprosy manipulate the immune system to infect the body and cause nerve damage. Until now, little was known about how these bacteria work to spread disease, but with a new model organism to study them, a team of researchers is breaking down the mystery.
From the University of Cambridge in collaboration with the University of Washington, the University of California Los Angeles, and Harvard University, scientists are now using zebrafish to study leprosy, a completely new approach to studying the condition, which some people know as “Hansen’s disease.”
Mycobacterium leprae are the painfully slow-growing microorganisms responsible for the disease that impacts the nerves, skin, eyes, and lining of the nose. It can take up to 20 years for an infected person to begin experiencing symptoms, but leprosy can be cured if detected and treated early enough. However, untreated leprosy leads to paralysis and blindness.
According to the World Health Organization (WHO), leprosy affects just 250,000 people around the world every year, a number that has decreased dramatically over the last several decades. In comparison, the WHO reports that in 1985, 5.2 million people had leprosy. The development of the drug dapsone in the 1940s was the first major breakthrough in the treatment of leprosy.
Using zebrafish, researchers wanted to find out how exactly M. laprae bacteria were infecting cells and damaging nerves. From past studies, they knew that nerve damage from leprosy, which is irreversible, is due to the destruction of the myelin sheath, which provides a protective, insulative layer over nerve fibers. Researchers believed this destruction occurred because bacteria invaded the cells responsible for producing myelin, but the recent study revealed that there more to it than that.
Researchers began with genetically modified zebrafish, altered so that their myelin fluoresces a bright green. Next they injected bacteria into nerve cells, and because youth zebrafish are transparent, what happened next was clearly visible. M. laprae infected macrophages, immune cells that typically engulf and digest pathogens. However, while M. laprae were indeed inside the macrophages, the bacteria were not destroyed.
"These 'Pac-Man'-like immune cells swallow the leprosy bacteria, but are not always able to destroy them," explained Professor Lalita Ramakrishnan. "Instead, the macrophages, which should be moving up and down the nerve fibre repairing damage, slow down and settle in place, destroying the myelin sheath."
How does macrophage-based myelin damage occur? PGL-1, a molecule employed by M. laprae, is produced to make changes in the macrophage. The result is overproduction of nitric oxide, causing damage to the cells’ mitochondria. Produced in proper amounts, nitric oxide is helpful to the immune agenda - too much and it’s toxic.
"The leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry," Ramakrishnan said.
The destruction of the myelin sheath that characterizes nerve damage in leprosy is very similar to the damage that occurs in cases of multiple sclerosis. Additionally, zebrafish are used to study another disease caused by a mycobacterium, tuberculosis. "Our study appears to place leprosy in the same category of these diseases,” explained Dr. Cressida Madigan from the University of California, Los Angeles.
In light of the study’s findings, the authors maintain that early detection is still key for treating leprosy. But perhaps reversing nerve damage is possible, despite the severe damage done to the myelin sheath.
“We would like to understand how to change that,” Ramakrishnan said. “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 present study was published in the journal Cell.