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From: TSS ()
Subject: Re: Cells infected with scrapie and Creutzfeldt–Jakob disease agents produce intracellular 25-nm virus-like particles
Date: February 7, 2007 at 8:01 am PST

In Reply to: Cells infected with scrapie and Creutzfeldt–Jakob disease agents produce intracellular 25-nm virus-like particles posted by TSS on January 31, 2007 at 10:28 am:

Published: Wednesday, February 7, 2007


Yale M.D. makes leap in mad cow research

Misha Mihailova

Staff Reporter

Though challenging the accepted theory of the causes of mad cow disease may seem like madness itself, a team of researchers from the Yale School of Medicine has announced potentially groundbreaking findings concerning the origins of the disease.

Yale School of Medicine professor Dr. Laura Manuelidis, the head of neuropathology at the school, and her team of researchers recently published a report in the Proceedings of the National Academy of Sciences asserting that a virus, rather than prion proteins, is the cause of mad cow disease in animals and Creutzfeldt-Jakob disease in humans. These spongiform encephalopathies of the brain have traditionally been thought to be caused by prions — abnormal proteins that convert healthy proteins to the disease state. But the new study suggests prions may simply be part of the late stages of the diseases, not part of the causes.

Transmissible spongiform encephalopathies affect the brains and nervous systems of victims, including sheep, deer and humans. The term ”spongiform” comes from the fact that the infection causes neurons to die, leaving tiny holes in the brain so that it eventually resembles a sponge. Humans afflicted with the incurable degenerative disease show memory and personality changes and sometimes problems with movement. Mad cow, the cattle version of the disease, has achieved infamy because the infectious agent in cows appears to be the cause of vCJD, a variant form of CJD in humans.

The research team’s goal was to try to identify viral particles in infected cells. They infected cell lines with either scrapie (a sheep disease related to mad cow) or CJD agents and found virus-like particles that did not contain prion protein. An abundance of these particles was related to high levels of infectivity, which was not true of the presence of prion proteins.

“People hypothesize that prion proteins are infectious, but they’re probably part of the disease, not the infectious agent itself,” Manuelidis said.

The virus-like particles had been found by other researchers but were largely ignored. They were first identified in 1968 in synaptic regions of scrapie-infected brain and later found in many other animals with different TSEs. But Manuelidis said that researchers apparently forgot about them once the prion hypothesis became dominant.

“I had totally forgotten about them, too,” she said. “But after we found the 25-nanometer particles, I went home and remembered I’ve seen these before. I went back to the old journals from the ’70s and there they were.”

Manuelidis said part of the reason for the neglect of the virus-like particles is that in previous studies, they were always found in degenerating brain tissue, so it was impossible for scientists to draw accurate conclusions about them. What allowed her to collect relevant experimental data was the fact that her team observed the particles in highly infectious tissue culture cells.

“We saw them in tissue culture cells that weren’t degenerating,” she said. “The infected cells were as healthy as the uninfected cells that had no 25-nm virus-like particles.”

The study is a work in progress, and the researchers want to conduct more experiments with tissue cultures to gather further evidence and learn more about the particles. Manuelidis said that since it is easier to work with a simplified cell system than with infected animals whose brains are degenerating, tissue culture experiments can be used to identify essential features of the infectious agent and clarify the way in which the particles invade cells. Her team will use the tissue cultures to purify the virus-like particles more completely.

“In the future, we will try to isolate the particles from tissue cultures and characterize what is in them,” she said.

The team’s specific viral particle hypothesis suggests new avenues for treatment and vaccines, Manuelidis said. If they are successful in rapidly measuring infectivity in tissue culture, they will be able to gain better understanding of possible remedies. She even pointed out that prion proteins, while not the infectious agent, are probably essential receptors for replication and growth of the TSE virus.

”The infectious agent needs prion proteins to grow,” Manuelidis said. “This means targeting the prion protein may also be a useful therapeutic step.”

Researchers at other universities pointed out that the Yale study does not definitely prove the viral hypothesis, nor does it fully disprove the prion hypothesis.

Tricia Serio, an assistant professor of molecular biology, cell biology and biochemistry at Brown University, said that while the research is intriguing, the viral hypothesis still needs to be directly proven. She also pointed out that there are many examples of protein-based phenotypes, like the one described in the prion hypothesis.

“For example, we study prions in yeast, and work from the Weissman, King, Liebman, Saupe and Wickner labs has shown that the transfer of recombinant protein produced in bacteria is sufficient to induce a heritable phenotype in yeast,” she said. ”This is direct proof of a prion mechanism for the yeast traits.”

Surachai Supattapone, associate professor of biochemistry and medicine at Dartmouth University, said that the next challenge for Dr. Manuelidis’ group will be to isolate and identify a specific virus that can cause transmissible spongiform encephalopathy. He said, however, that there is still work ahead for prion protein researchers.

“Proponents of the ‘protein only’ hypothesis — which is also not proven — will need to demonstrate that purified prion proteins alone can fulfill Koch’s postulates [a set of criteria for establishing a causal relationship between an infectious agent and a disease] to prove their alternative claim,” he said.


http://www.yaledailynews.com/articles/view/19788


TSS



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