An embargoed press conference took place in S o Paolo, Brazil Monday at the State Governor's Palace. Its agenda centered on two related articles in the forthcoming October 2003 issue of Nature Genetics, released online Sept. 14.
The state governor announced to some 100 attendees that the government last week filed patent applications at the U.S. Patent Office covering drug and vaccine candidates, aimed at attracting commercial partners. The scientific director of the S o Paolo Research Foundation, Sergio Verjowski-Almeida, introduced the Nature Genetics papers, and welcomed the conference for strategizing control of schistosomiasis. Almeida is principal author of the journal article titled "Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni." (Acoelomate describes the hollow cavity of one parasite species.)
But that's just the half of it. An accompanying second article in the same Nature Genetics bears the title "Evolutionary and biomedical implications of a Schistosoma japonicum complementary DNA resource." Its senior author is genomicist Ze-Guang Han, at the Chinese National Human Genome Center in Shanghai. Among its co-authors is tropical medicine specialist Paul Brindley at Tulane University in New Orleans. He is an active collaborator with the Chinese researchers.
Japonicum and mansoni are two of the three schistosoma species that infect animals. The third, Schistoma hematobium, attacks humans. Second only to malaria, schistosomiasis is the most ubiquitous and destructive infection that afflicts the human race. It kills an estimated 800,000 men, women and children a year. (The disease also is known as bilharzia and, among alcoholics, cirrhosis of the liver, or hepatic fibrosis.) In the U.S., more than 400,000 patients - mostly immigrants and returning travelers - are infected with the pathogenic liver flukes of schistosomiasis.
"That water-borne parasite doesn't worm its way into its victim's liver or circulation all by itself," Almeida told BioWorld Today. "The worm is about 1 centimeter long by 1 to 2 millimeters thick. Most people in tropical climes go barefoot so they pick up a freshwater snail, of the genus Biomphalari. This mollusk transmits the S. mansoni or japonicum parasite into the victim's blood, en route to the liver. That pathology may prove fatal. Tens or thousands of them stay there and deposit eggs that will clog the microvessels of the liver and impair its circulation. There they will reside latent for three to 37 years or so.
"The disease is transmitted," Almeida continued, "when adults, such as fishermen or irrigation workers, or school-age children, go into water that contain the snails. They are infected and carry cercaria - free-swimming larvae. In heat or sunlight, these pathogens leave the snails. They swim actively and bore through the skin by means of enzymes on its epidermal surface."
Schistosoma, Second Only To Malaria
"Our finding, as we report in Nature Genetics," Almeida went on, "is that we discovered a number of molecules that are tools to open windows of opportunity in the well-adjusted parasites, which live for years in their human hosts. Ten percent of infected people suffer the acute disease, and 10 percent of these - 2 million people in the world - will die from the malady. Schistosomiasis is not an acute infection, like malaria. Rather, it's parasitism, wasting disease that will jeopardize the lives of the children with destruction of their liver."
A broad-spectrum antihelminthic agent, praziquantel by name, is effective against all schistosome species in humans, and has few adverse side effects. But drug resistance is a looming hazard. "In Senegal," Almeida observed ominously, "resistance to the praziquantel drug has already been documented." To date, despite many attempts at vaccines, none has taken hold. "Our first vaccine candidate," Almeida recounted, "is a family of toxins that the parasite secretes. They interfere with immune responses of humans and elicit allergenic reactions. In our laboratory, we have found four genes that encode wasp venom allergens. The parasite also secretes anticoagulant serpent venom - all putative vaccine targets.
"Vaccine candidates have been tested," Almeida added, "but they yield 30 percent protection, which is considered too low. And it, too, may develop resistant forms. But if we combine more than one of the possible vaccine candidates, we might do better. The successful vaccination of both rodents and primates with attenuated larvae indicates that the goal is feasible. But it will take from five to 10 years to test new vaccines with the molecules we have found."
20-Year Vaccine Quest; No KO Punch
"Historically," Brindley, the Australian collaborator with the Chinese scientists, remarked, "People have been looking for new vaccines against schistosomiasis for maybe 20 years. There are a number of well-characterized proteins, but so far no one has come up with something that's really a knockout punch. Quite a lot is known about the epidemiology of these three major disease species," Brindley went on. "There's the S. japonicum, which is endemic in the Asian countries. Then there are two that originated in Africa, S. mansoni and the third one, Hematobium mansoni. It probably came to the Western hemisphere - no doubt to the Americas - with the slave trade from about the 1600s. It just so happened that there were just the right kind of snails to support the parasites.
"S. hematobium occurs in Africa and the eastern Mediterranean, where it causes urinary schistosomiasis," Brindley recounted. "The cercariae adapt to the mammalian environment. Schistosomes are dioecious - sexually dimorphic as adults. Developing male and female worms depart the lungs and move into the hepatic portal system to mature, pair up and migrate upstream to the intestines. Eggs produced by female worms are discharged with the feces or urine."
Co-authors at the Chinese National Human Genome Center sequenced and annotated more than 13,000 genes that are known to be expressed in Schistosoma japonicum - the parasite that causes schistosomiasis in China and other Asian countries. S. japonicum has a total of approximately 15,000 genes. Almeida and his colleagues at the University of S o Paolo sequenced and analyzed 92 percent of the estimated 14,000 genes of Schistosoma mansoni, which is endemic to Africa, the Caribbean and South America.
"The disease has spread to the central part of Brazil," Almeida noted, "where construction of a large dam for hydroelectric power plants was started 10 years ago. The workers were brought from the northeast, and became infected because the snails were in the lake water."