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Polluted blood fails to deliver infection.

Prions, the cause of mad cow disease and related illnesses, cannot dock easily on the shores of the brain. Like passengers stuck on a large ocean liner in a rocky lagoon, they need a landing vehicle, new research suggests.

Although the chemical nature of prions and the method by which they produce disease remain controversial (SN: 9/24/94, p. 202), a molecule called prion protein (PrP) plays a central role. It exists in several versions, only some of which provoke trouble.

Healthy people carry normal PrP molecules on nerve cells but can acquire deviant ones by ingesting tainted meat. The infectious agent travels to the brain, where it inflicts its hallmark damage--transforming this organ into a hole-ridden sponge.

Although scientists have known that the agents of destruction must spread from the gut to the central nervous system, the details of this journey remained vague. Now researchers have discovered that the infectious material must make several connections. They report that prions; cruise around the body in blood cells, but these vehicles cannot deliver them directly to the brain. Adriano Aguzzi of the University of Zurich and his colleagues describe their work in the Sept. 4 Nature.

One current hypothesis holds that when a person or animal acquires an altered form of PrP, the misbehaving protein causes even normal PrP molecules to glom on to each other, thereby wreaking havoc in nerve cells. In fact, to succumb to disease, animals must have normal PrP in their cells: Mice engineered to lack these proteins resist infection.

"It's like dominoes," says Aguzzi. "You throw the first one over and they go thk, thk, thk along the surface of nerve cells." Cells that don't contain normal PrP break the link in the infectious chain of events, he says.

To examine that chain, Aguzzi's group in previous work implanted a piece of brain containing normal PrP into the head of a mouse that lacks PrP. Infectious material caused damage to the implanted tissue only when the researchers delivered the agent directly to the brain. When injected into the blood-stream, the altered PrP caused no harm to the grafted tissue.

Scientists explained this result by saying that blood cells in these mice don't contain any normal PrP and therefore can't carry the infection to the brain, says Pierluigi Gambetti at Case Western Reserve University in Cleveland, who studies an inherited prion disease called fatal familial insomnia, which makes people unable to sleep and eventually causes death.

In the new study, the researchers replaced the bone marrow of mice that lack PrP with bone marrow containing normal PrP, They then injected infectious material into the mice, expecting that the blood cells, now equipped with PrP, would convey the infection to the brain. Instead, the graft remained healthy--even though the corrupt protein converted normal PrP to the altered form inside blood cells.

"The big happening is what did not happen," says Gambetti. "The animals did not get infected, even with abnormal prions running around in the blood."

The investigators concluded that, to complete the link with the brain, some other tissue needs to produce PrP.

"This is good news because it means that prions stay where they are unless there are PrP-expressing cells that pick them up and move them around," says Aguzzi. "I'd like to identify the bottleneck and do something to block it [in people exposed to prions]."

Other groups have also attempted to trace infectious prions through the body. Their results point to the peripheral nerve cells, those outside the brain and spinal cord, says Aguzzi. Prions may require normal PrP in these cells in order to migrate to the brain.

In his efforts to devise therapeutic interventions, Aguzzi is focusing on the blood cells that harbor infectious PrP. In principle, people who have eaten contaminated meat could take drugs that attack these cells. Researchers have not yet identified which of the many types of blood cells carry the agent.

"There's a tremendously long incubation period between ingestion and brain infection--possibly even 20 or 30 years," says Aguzzi. "We have a window of opportunity during that time."
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Title Annotation:Bovine spongiform encephalopathy
Author:Strauss, Evelyn
Publication:Science News
Date:Sep 6, 1997
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