ARTICLE IN BRIEF
Japanese macaque monkeys infected with a newly identified virus develop a progressive disease characterized by paresis in one or more limbs, ataxia, or ocular motor paresis — providing a potential new animal model for multiple sclerosis research.
The multiple sclerosis (MS) community has a surprising and important new animal model, the Japanese macaque monkey, which could provide a tantalizing new clue to the etiology of the human disease. The monkey develops an MS-like demyelinating disease after infection with a newly characterized virus, according to a study that appeared online before print in the Annals of Neurology.
“The new model offers the opportunity to try to understand the pathogenesis in an animal a lot closer to humans, and to test therapeutics,” said Neurology Today Associate Editor Kenneth L. Tyler, MD, who was not involved in the research. “It also raises the possibility that a related virus could potentially be playing a role in human disease,” said Dr. Tyler, the Reuler-Lewin Family Professor and chair of neurology at the University of Colorado-Denver.
The virus is a previously unknown gamma-herpesvirus. Infected monkeys develop a progressive disease characterized by paresis in one or more limbs, ataxia, or ocular motor paresis. It was first observed in the monkey colony at the Oregon National Primate Research Center in Beaverton, OR, in 1986, and has developed spontaneously in one to four monkeys per year since then, affecting a total of 56 animals.
The disease, called Japanese Macaque encephalitis (JME), affects male and female animals equally, with no seasonal pattern in development. The median age of symptom onset is about four years, ranging from several months to 26 years; macaques can live to be over 30 years.
Most animals were euthanized shortly after developing symptoms, because they were unlikely to be accepted back into the colony, according to Dennis Bourdette, MD, research professor and chair of neurology at the Oregon Health and Science University in Portland, who was a member of the research team. The median interval between onset and euthanasia was six days. Several animals did recover and were returned to the colony before succumbing to a relapse of JME after an interval of several months to several years.
Similarities to MS were also seen on MRI scans, performed on several animals using a 3-Tesla instrument, similar to that used in humans. The scans showed hyperintensity in the upper cervical spine, cerebellum, and cerebrum “consistent with active neuroinflammation and similar to the MRI findings of acute lesions in MS,” the researchers reported. Necropsy results also showed strong similarities to MS, with multifocal lesions containing T cell and macrophage infiltrates, with demyelination, limited remyelination, depletion of oligodendrocytes, and axonal degeneration.
Lesioned spinal cord tissue, when cultured with monkey fibroblasts, yielded a novel virus. The DNA sequence of the virus grouped it with the herpes viruses, and showed it to be closely related to a known rhesus macaque virus called rhadinovirus. The researchers termed the new virus JM rhadinovirus (JMRV). No JMRV has been isolated from brain tissue in non-affected Japanese macaques.
The origin of the virus is unknown, said a virologist on the team, Scott Wong, PhD. “This could have been a latent infection that re-emerged, or it could have been introduced into the colony. We are not really sure yet.”
The researchers are now completing experiments to prove that purified virus can cause the disease in healthy animals. The results of those experiments have not yet been released, but, Dr. Bourdette said, “I am confident the virus induces the disease. I am confident [the experiments] will yield a positive result.”
They are also looking at the presymptomatic phase of the disease, performing MRIs on healthy animals and then following them. “We can see gadolinium-enhancing lesions in the brains of animals without symptoms,” Dr. Wong said. Several such animals have gone on to develop JME over several years.
FINDING A POSSIBLE CAUSE FOR MS
The relationship of JME to MS is still unknown, said Dr. Bourdette. “For decades, it has been thought a virus might cause or at least trigger MS.” Multiple candidates have been proposed, but none have been confirmed. “That may be because a virus isn't involved,” he said. “But another possibility is that it is caused by an unusual virus, one that is difficult to find, and perhaps not previously described, and it's a matter of not knowing how to look.”
“The first and potentially most exciting thing about the discovery of JMRV as the cause of Japanese macaque encephalitis is that it is possible that a human version of this virus, one that has previously been unrecognized, is actually the causative agent in MS. We now have a new class of viruses that can cause an MS-like disease in non-human primates, and this will give us the molecular tools to look in MS tissue and MS blood samples to see if there is a similar virus involved in the disease. That's the big hope,” said Dr. Bourdette. Those experiments are in their beginning stages.
“Even if this class of viruses doesn't pan out as a causative agent, this is a unique model that will allow us to really study how a virus can trigger an MS-like disease in a nonhuman primate,” Dr. Bourdette added, noting that mice are different enough immunologically that inferences from them can only be taken so far. And it is simply much easier to perform MRI and other procedures on larger animals. Finally, if the model is fully developed, it may prove useful to test new therapies, especially those aimed at repairing damaged tissue, Dr. Bourdette suggested.
The study was supported by a grant from the NIH, the Research Enrichment Award Program of the Department of Veterans Affairs Biomedical Laboratory Research and Development, the OHSU Multiple Sclerosis Center, and the United States Department of Defense.
“This is a very interesting new animal model of an MS-like disease,” said Dr. Tyler. “I think it's important for a variety of reasons. It replicates many of the cardinal features of MS, though not perfectly. We haven't had a model of a spontaneous inflammatory demyelinating disease in a non-human primate before. We've largely been dependent on murine models, and each of those has issues.” Nonetheless, he said, “this doesn't obviate the importance of those other models,” especially because of the cost and regulatory issues involving primate research.
The most intriguing aspect of the monkey disease may be that, like human MS, it occurs naturally. “To have a disease that occurs spontaneously, without injection of protein, is really interesting and important because it may provide some insight into how the same process occurs in humans,” Dr. Tyler said. “And the possibility that this previously unknown virus, or one like it, may be involved in causing multiple sclerosis is a fascinating conjecture.”