5 September 2008

Scientists create species-jumping hybrid prions

by Kate Melville

In research with profound implications for public health, scientists have created entirely new strains of infectious prions in the laboratory by simply mixing infectious prions from one species with the normal prion proteins of another species. According to the scientists' report in Cell, the new prions produced symptoms in laboratory animals that differ from any known prion strain found in nature.

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are infectious neurodegenerative diseases affecting the brain. Unlike conventional infectious microorganisms, the infectious agent in the case of prion diseases consists exclusively of a misfolded form of the prion protein. Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans, along with scrapie in sheep and bovine spongiform encephalopathy (BSE, aka mad cow) in cattle.

In this new work, the researchers found that prion strains produced by combining normal hamster proteins with infectious mouse proteins can infect hamsters and vice versa. Although they are both rodents, prions from one of the two species normally don't readily infect the other, a common phenomenon amongst prions known as a species barrier, the researchers explained.

"We are forcing the system by putting everything together, but this suggests that the variety of possible prions is really very large," said Claudio Soto of the University of Texas Medical Branch. "We shouldn't be surprised if new barriers are crossed and new prions arise. There is the potential for a large variety of new infectious prions - some of which may have dramatic effects."

The same research team had previously reported the generation of infectious prions by amplification of prion misfolding in the test tube. In those experiments, they used a technology called protein misfolding cyclic amplification (PMCA) that mimics some of the fundamental steps involved in the replication of infectious prions in living animals, but at an accelerated rate. The method involves placing small quantities of infectious prions with large quantities of the normal protein from the same species together, allowing the infectious form to imprint on the normal form and thereby replicate itself.

Now, they have shown that the same method can generate new strains when infectious prions from one species are mixed with normal prion proteins from another species. The finding provides strong evidence that the imprinting of disease-causing prions on normal forms can overcome species barriers, and doesn't require any other infectious agent.

This new work has profound implications for public health, says Soto. "One of the scariest medical problems of the last decades has been the emergence of a new and fatal human prion disease - variant CJD - originated by cross-species transmission of BSE from cattle. Our findings suggest that the universe of possible prions is not restricted to those currently known but that likely many unique infectious foldings of the prion protein may be produced and that one of the sources for this is cross-species transmission."

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Source: Cell Press