Newly Discovered Protein Could Lead to Vaccine for Schistosomiasis

By William J. Cromie

Gazette Staff

Parasitic worms known as schistosomes, or "blood flukes," are strange little beasts that sicken some 200 million people around the world.

Adult females of this microscopic species live inside a groove in the males, and the close-knit couples reside in blood vessels surrounding the intestine or bladder of humans. Once the parasites start to produce eggs, their unfortunate hosts can suffer flu-like symptoms -- high fever, chills, aches, and pain. This condition can progress to stomach or back pain, enlargement of the liver or spleen, and, eventually, to bladder tumors and liver damage.

The disease, known as schistosomiasis, spreads via eggs that the "groovy" couples produce. The eggs pass through the walls of human blood vessels and into the intestine or bladder, from which they are evacuated directly, or through sewage, into lakes, rivers, and canals. These eggs hatch in the water, then grow into hairy larvae that infest freshwater snails.

The larvae grow into tadpole-like youngsters, which leave their snail hosts then burrow into the bloodstreams of people swimming, bathing, or otherwise coming into contact with the waters they populate.

Such invasions occur in tropical countries. Despite strict sanitary regulations and attempts to eradicate their snail intermediates, schistosomiasis is the second most debilitating parasitic disease in the world, after malaria.

The ideal solution would be an effective vaccine. Last month, a team of scientists from Harvard and the University of Zurich, Switzerland, took a significant step in that direction. They discovered a protein complex that schistosomes need in order to take up nutrients from blood and keep themselves alive. A weakened version of this protein, injected into people, could alert their immune systems to fight off the parasites.

The discovery could also have a more general and basic impact on biology because human cells use related proteins to take up nutrients such as sugars and the amino acids needed to make other types of proteins.

"Similar proteins transport amino acid molecules from blood into both schistosome and human cells," explains Patrick Skelly of the Harvard School of Public Health. "Conceivably, defects in the human transporters could be involved in various conditions that make us ill. We are looking into this along with the possibility of using our discovery to develop a vaccine against schistosomiasis."

A Boring Head

The tadpole-like schistosome larva loses its tail as it bores into people's bloodstreams but keeps its head and gut. The invader also grows a new skin studded with tube-like transporters. Skelly, an instructor in tropical public health, and Charles Shoemaker, an associate professor of immunology and infectious diseases, use a powerful microscope to track the formation of this skin and its built-in nutrient transporters.

To understand how the transporter works, Shoemaker and Skelly used special laboratory techniques to induce frog eggs to make the schistosome protein. They wanted to see if these eggs took up more nutrients than untreated eggs. They did not.

Meanwhile, the Swiss team under Francois Verrey were working on the same problem. They came up with the idea that the transporter needs a second protein to work properly. When the Harvard team got frog eggs to make both this second protein and the schistosome protein, that did the trick. Eggs that got this protein cocktail took-up more nutrients than those that didn't get it.

Shoemaker and Skelly also identified a human protein that resembles the schistosome transporter. When they used it with frog eggs, it worked as well as the parasite's protein.

"These experiments have led to the discovery and characterization of a broadly interesting family of amino acid transporters," notes Skelly. These proteins work in schistosomes, frogs, and humans when associated with a second, helper protein. "Clearly, the new family must be important enough to be preserved during millions of years of evolution."

Making A Vaccine

The next step is to turn this knowledge into a useable vaccine. "First, we will try to test the schistosome transporter alone as a vaccine," Skelly says. "We'll also try other nutrient transporters we have found. Second, we want to purify the natural helper protein used by the schistosome."

Purifying a protein combination embedded in the skin of a microscopic parasite is no easy job. One way to do it involves cloning the genetic material that carries instructions needed for a body to make the combination. Injecting the genes rather than the proteins directly into a human might produce enough of a stimulus for the immune system to reject any invaders that later burrow their way into the body.

Skelly and his colleagues expect scientists to pay much wider attention to this new family of proteins. "Like schistosomes, every animal needs nutrients like amino acids to survive and reproduce," Skelly notes. "We knew different types of human cells take up various amino acids, but until now we had no idea about the molecular details of how they do it.

"I think that many people will start searching for relatives of this protein family," he continues. "They will try to determine what members transport what amino acids into what cells, as well as what medical problems result when the transports don't function properly."