Leprosy—also known as Hansen’s disease—is a chronic infectious disease caused by Mycobacterium leprae (and, less commonly, Mycobacterium lepromatosis) that results in severe, disfiguring skin sores and peripheral nerve damage in the arms, legs, and skin areas around the body. It’s most prevalent in the developing world, where living conditions are poor and people struggle to access sufficient healthcare. Although the disease is curable and early treatment averts most disabilities, there are many barriers that prevent people from accessing treatment. In addition to the historical stigma associated with leprosy, there are problems with misdiagnosis—infected people and many medical professionals do not recognize the symptoms of the disease, so therapy is delayed until a correct diagnosis is made.
Leprosy starts by damaging the small nerves in the skin’s surface. The first outward sign is usually discolored patches where there is no feeling. If treated at this early stage, damage or disability is unlikely. If left untreated, leprosy goes on to damage the large nerves in the elbow, wrist, knee and ankle. The resulting damage can lead to loss of sensation in the hands and feet and muscle paralysis, which causes clawed fingers and foot drop. Loss of sensation in the hands and feet means everyday activities are fraught with danger—burns go unrecognized and stones in shoes unnoticed leading to ulcers developing. These can be difficult to heal and become infected, often leading to the shortening of fingers and toes or ultimately, amputation of limbs.
Although the disease was one of the most dreaded of medieval times, and has been around for thousands of years, very little is known about its biology. One of the reasons is that M. leprae and M. lepromatosis are difficult to study, as they grow poorly in culture. In addition, there are no good animal models of leprosy. Although M. leprae can grow in the footpads of mice, it does not cause nerve damage. It does so in armadillos, but these animals are rarely used in research. Now, by using zebrafish as animal model in a new study published in the journal Cell (A Macrophage Response To Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage In Leprosy), scientists have been able to understand how M. leprae causes nerve damage.
Previously, scientists believed that the nerve damage in leprosy was caused by M. leprae infecting Schwann cells, specialized cells that produce myelin, resulting in demyelination, or the stripping away of the myelin sheath. The myelin sheath is the protective insulation that protects the axons, or nerve fibers—the long, slender projection of a nerve cell, or neuron, that typically conducts electrical impulses away from the neuron’s cell body.
For the new study, scientists used transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. They found that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons. Macrophages, or big eaters, are immune cells that, among other major functions, consume and destroy foreign bodies, cellular debris, and all unwanted material. The scientists also showed that a molecule known as phenolic glycolipid, or PGL-1, present on the surface of M. leprae, “reprograms” the macrophage, causing it to overproduce a potentially destructive form of the chemical nitric oxide, which damages mitochondria—the “batteries” that power nerve cells.
Lalita Ramakrishnan, senior author of the study, said in a press release: “These ‘Pac-Man’-like immune cells swallow the leprosy bacteria, but are not always able to destroy them. 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. The leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry. It then starts spewing out toxic chemicals. Not only does it stop repairing damage, but it creates more damage itself.”
Cressida Madigan, lead author of the study, added: “We know that the immune system can lead to nerve damage—and in particular to the myelin sheath—in other diseases, such as multiple sclerosis and Guillain–Barré syndrome. Our study appears to place leprosy in the same category of these diseases.”
Watch the video below for an illustrated explanation by the study authors of how M. leprae damages nerves.