|viruslike particles with dense centers (as at arrows) collect in membrane bound arrays in an infected cell.|
The alternative view that a virus causes spongiform encephalopathies of the brain, such as “mad cow” and Creutzfeldt-Jakob (CJD) disease, rather than prion proteins, which are normally produced throughout life, is bolstered in a new study by Yale School of Medicine researchers.
The report published online January 29 in the Proceedings of the National Academy of Sciences provides evidence that a virus causes these diseases, which are manifested by devastating holes, or sponge-like spaces, in the cerebral cortex. The conclusions counter the now conventional view that abnormally folded prion proteins are infectious, and instead suggests that abnormal prion proteins are late stage footprints left by the virus.
The lead author, Laura Manuelidis, M.D., professor and section chief of neuropathology, infected cell lines with either scrapie or CJD agents. Scrapie is a degenerative disease that affects sheep and goats and is related to bovine spongiform encephalopathy, or “mad cow” disease.
Examining the cultures using electron microscopy, Manuelidis and her co-authors found an abundance of 25 nm virus-like particles. They also found that the particles did not bind antibodies for the prion protein, indicating they were not composed of prion protein. The development of the particles was independent of pathological changes or neuronal specialization, and preparations with an abundance of these particles correlated with high levels of infectivity, whereas the presence of prion proteins did not.
“Although much work remains to be done, there is a reasonable possibility these are the long sought viral particles that cause transmissible spongiform encephalopathies,” Manuelidis said. “The abnormal protein is probably not infectious, but is a pathological result an infectious virus binding to this host protein. Highly infectious cultures are ideal for fundamental molecular studies of this virus, as well as rapid therapeutic, preventive, and vaccination approaches.”
Co-authors include Zhoa-Xue Yu, Nuria Banquero, and Brian Mullins. The work was supported by a National Institutes of Health grant and by a U.S. Department of Defense grant.
PNAS (online early edition doi 10.1073)