1. Leprosy is a bacterial infection marked by nerve damage.
2. The cause of that neuronal mayhem is a too-vigorous immune response.
3. Ergo, treatment of leprosy patients is largely based on bridling their immune system.
This medical syllogism is neat, plausible and wrong at least in critical part. So reports microbiologist/cell biologist Anura Rambukkana in today’s Science, dated May 3, 2002.
“That nerve damage,” he told BioWorld Today, “previously thought to be a byproduct of the immune system’s reaction to the leprosy bacterium, Mycobacterium leprae, we find to be a direct result of the leprosy bug attaching itself to specialized nerve cells called Schwann cells. They are the glia or supporting cells of the peripheral nervous system, which leprosy attacks by stripping axons of their insulating myelin.”
“Schwann cells,” Rambukkana explained, “come in two versions. One makes the myelin sheath around the axons of larger neurons. That insulator can facilitate rapid nerve-impulse conduction. The other Schwann cells, which serve the smaller-caliber neurons that have no myelin fibers, provide neuroconduction that is very slow. For instance,” he pointed out, “if you touch a hotplate with your fingers, you feel the pain a little bit later. This is the slow conduction. Whereas if you can see something, say you touch your leg, you can sense it immediately because this is very rapid nerve conduction. In a millionth of a second you get the message. And this is done mostly by myelin insulation. It’s like around an electrical wire. So the insulation part is very important for the stability of the nervous system.”
Rambukkana’s article in Science bears the title: “Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells.”
“What we report,” he said, “is that we have an agent namely the leprosy bacterium which can induce early nerve damage similar to many neurodegenerative diseases. Those diseases, such as multiple sclerosis and Guillain-Barré syndrome, have lost much of their myelin, which carries the high propagation of nerve impulses that can be very rapidly transmitted from the brain to the muscles and skin. In the early stage of the disease process, we have no idea what is happening.”
Bacteriological, Neurological Myelin Foes
“A similar phenomenon is taking place in bacterial infections. One of the characteristic infectious diseases, which causes such nerve damage, is leprosy,” he said. “We determined that M. leprae damages the myelin sheath of the nerve fibers very early in the course of the infection something nobody knew before was the case. Rather, everybody thought that this phenomenon is due to the immune response. Here we show that this effect can be induced by the bacteria without involving a single immune cell. This suggests that in the early stage of neurodegeneration, you don’t need the immune response to activate the disease.
“That is what the hypothesis has been in multiple sclerosis and other neurodegenerative diseases,” he noted. “By using immune-deficient mice, and an in vitro system where we could generate the neurons with the myelin sheath in culture, we demonstrated that without any immune cells, the bacteria induced such a demyelinating process which resembles the other diseases, such as MS.
“In our in vivo experiment,” Rambukkana recounted, “we simply injected the live leprosy bacteria, and their lifeless bacterial products, into a standard immunodeficient mouse model. Within 72 hours, we could see significant demyelination damage to their nerves. Using a co-culture’ system developed by co-author James Salzer at New York University, M. leprae produced significant damage to the myelin sheaths 24 hours after attaching to the nerves. Unexpectedly,” he added, “the bacterium doesn’t have to enter the cell to cause this myelin degeneration. Instead, it hides out in the supporting cells that enclose non-myelin fibers, poised to initiate later attacks.”
“This suggests,” Salzer said, “that binding of M. leprae to the surface of the myelin sheath is sufficient to induce myelin breakdown presumably by activating signals inside the cell. Such signals could also be activated in other diseases that cause demyelination.”
“There are more than 10 million cases of leprosy in the world today,” Rambukkana observed. “Antibiotics can cure the disease bacteriologically. But the problem is that the neurological damage is irreversible. Patients who have had the disease still have a problem. Those inert bacterial products, which remain inside, are unable to get out easily. And those products can continue to cause the nerve damage. That is what we have shown in this Science paper. We don’t need the live M. leprae to cause leprosy. We can bring on the disease by the cell-wall fraction of the bacterium its product which alone can cause this pathology.
“This is fascinating, because the leprosy bug does not kill the nerve cells Our study shows that early infection is very important because this itself can cause the damage, which can have effects in the later stage, by perturbing the whole neural microenvironment.”
On Track Of Diagnostic Markers
Rambukkana said, “There is no diagnosis for the early stage in any neurological disease. We only diagnose MS when the patient cannot move, cannot read. Once you diagnose it, the damage has already occurred. So this finding is a good tool that we can use for diagnosis. If you use a known pathogen that can cause similar damage, how it caused the lesion will help us to understand the early stage, which, I believe, can be useful as common diagnostic markers for many demyelinating neurodegenerative diseases of which there are 10 or 15 known.”
He and his co-authors are looking for a diagnostic marker to tackle the question: What should be done with suspected early stage leprosy, rather than go immediately to inflammatory immune cells? He pictures a putative clinical scenario in using those markers to diagnose a suspect patient: “Hey, this guy may have leprosy,” or, “This guy is more genetically prone to get neurodegenerative diseases.”
Foreseeing the future, he said: “Our plan is not to deal clinically with leprosy only but also to use this as a model for dissecting the molecular basis of the demyelination process. We are really focused,” he concluded, “on the wider application not on leprosy per se.”