Malformed proteins responsible for ailments like mad cow disease wreak their havoc by eating holes in the brain. Yet they are usually ingested when someone eats meat from an infected animal.
So how do these big brutes of a protein, known as prions, get from the stomach to the brain?
In a study being released Wednesday, scientists say they may have figured out how some prions can survive the human digestive system and make their way into the body: piggybacking on a normal protein that helps human cells store and transport iron.
Researchers didn't make a link all the way to the brain, but their findings help show how infectious proteins may be able to survive the acids and enzymes used in digestion and escape into the rest of the body via the wall of the intestines.
"Given the molecular size of prions, it is surprising that they can cross the epithelial cell barrier without any problem," said Dr. Neena Singh, an associate professor of pathology at Case Western Reserve University and the study's senior author.
Singh and fellow researchers found that prions from a human disease related to bovine spongiform encephalopathy, or mad cow disease, appear to be able to make their way through the intestines by hitchhiking with a normal protein called ferritin. Ferritin is used throughout the body to help cells store iron.
They relied on samples from the brains of two human patients that died from sporadic Creutzfeldt-Jakob disease, or CJD, a degenerative brain disorder that occurs spontaneously in about one of every 1 million people. The illness also occurs in a variant form, known as vCJD, thought to be caused when people eat meat from infected cows.
In a laboratory, the researchers exposed the human brain samples to chemicals that simulate the human digestive process, including the enzyme pepsin, which is a key element of the stomach's digestive juices. What was left over included a mix of the infectious proteins and ferritin, and that combination managed to cross through a simulated intestinal wall.
Other studies have shown that human digestion is able to absorb ferritin through the intestines. In this study, which appears in the Jan. 5 edition of the Journal of Neuroscience, prions were tied to ferritin even after they passed through the intestinal cells.
"We tried several times to purify a prion and realized there was just one protein we could not get rid of," Singh said.
It was not clear why this particular normal protein and the infectious protein were linked together, she said.
Both forms of CJD, and all similar ailments — often called prion diseases — are invariably fatal. Variant CJD, tied to mad cow disease, has killed about 140 people worldwide, with dozens more deaths projected. There is no way to confirm any prion infection until after a patient dies.
Edward Hoover, director of Colorado State University's Retrovirus and Prion Research Laboratory, said the new study helps illustrate one possible avenue for prions to make their way into the body, though there may be others.
"It makes a point that so far has not been studied as much in prion infection," Hoover said. "How does the agent get across to infect the first cells from the exterior world, which is how we think most creatures, including us, get infected."
Other studies planned
Different animals are infected by prion diseases in different ways, Hoover noted. While sheep appear to acquire scrapie, another prion-related ailment, through the intestine, deer seem to be infected higher up in the digestive tract.
Singh and other researchers are following up this study with a similar look at whether malformed prions from deer and elk infected with chronic-wasting disease can cross the intestinal wall.
If researchers can determine a single method by which prions enter the body on their way to the brain and nervous system, they may be able to look for medicine that could prevent such an absorption.
Hoover, who is working on a prion-based vaccine for deer, suggested that further experiments could be done to replicate the latest findings in animals, specifically transgenic mice that mimic human responses to prions.
Singh said her group had discussed animal studies, but first hopes to determine the precise method by which prions are travelling through intestinal walls. "Once you start feeding this stuff to mice, it's not easy to track it," she said. "But we are thinking about it."