"We found that the adaption is a prolonged and subtle process, and the early stages of it are very difficult to detect," says Bruce Chesebro, M.D., senior study author and researcher at NIAID's Rocky Mountain Laboratories (RML) in Montana. The results of his team's work are reported in the current issue of the Journal of Virology.
Scrapie and mad cow are examples of the rare, mysterious and fatal brain diseases known as transmissible spongiform encephalopathies (TSEs). Also known as prion diseases, they include chronic wasting disease in deer and elk and Creutzfeldt-Jakob disease in humans. The hallmark of TSE diseases is misshapen protein molecules that clump together and accumulate in brain tissue. Normal forms of these molecules, called prion protein, reside on the surface of brain cells, although no one knows their proper function. Abnormal prion proteins are the likely cause of the brain damage that occurs in TSE diseases. Scientists believe the misshapen prion proteins somehow induce normal prion proteins to form incorrectly. These abnormal molecules may spread the disease to new individuals. Alternatively, some scientists still believe that the disease may be initiated by a virus.
Dr. Chesebro and his team first inoculated mice with a strain of hamster scrapie, then watched the mice closely over a period of years. This group of mice never became sick, but the scientists found that the hamster scrapie agent persisted in these mice for years at levels too low for standard lab tests to detect. The scientists detected the hamster scrapie agent by injecting brain extracts from the mice into hamsters and watching to see if the hamsters came down with scrapie.
"All of the hamsters got scrapie, so we know that all of the mice were infected and carriers of the disease," says Richard Race, D.V.M., lead study author and RML researcher. "They didn't carry enough of the scrapie agent to show up in a lab test, but they did carry enough to re-infect the hamsters."
"We can't be certain these results would apply to other forms of TSE disease and other species," Dr. Chesebro explains, "but this finding suggests that TSE diseases may be more widespread than we thought. So we need to be more vigilant in monitoring the spread of TSE diseases. In particular, we need more sensitive diagnostic tests." Researchers at RML and other institutions around the world are already working on such laboratory tests, he notes.
The research also showed that, under the right conditions, scrapie gradually adapted to cause illness in mice over a period of one to two years. In the original group of infected mice, the scrapie agent never caused illness. But when the scientists transferred the agent from this original group of mice to additional groups, the disease grew stronger over time, making the newly infected mice sick. "The scrapie seemed to have learned how to deal with this new species, and it worked much better," says Dr. Race. "It replicated faster in additional rounds of mice and even became more lethal to them."
Furthermore, scrapie adapted in different ways in individual mice: the incubation periods varied widely, and the disease affected different parts of the brain. "It was not always the same pattern of adaptation," Dr. Chesebro says. "As the disease spread, there was a fanning out of many possibilities."
The researchers say their results might lead public health officials to reconsider the practice of giving animals feed made from the byproducts of other animals. Some evidence suggests that cattle in the United Kingdom contracted mad cow when they ate feed made from the bone meal of sheep infected with scrapie. Cows are no longer given such feed, but other farm animals are, the researchers say. "Because we have further confirmed that prion disease can adapt to new species, and because we've shown that process is slow and difficult to detect, it may be time to rethink this practice," says Dr. Race.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Reference: R Race et al. Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to human BSE/vCJD. Journal of Virology 75(21):10073-89 (2001).
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