Genomes Of Parasitic Flatworms Decoded

The research was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), and is published in the current issue of Nature. The genomic information obtained through these sequencing projects suggests ways to design drugs or other compounds targeted specifically at proteins or other gene products required by the parasite to find or survive in its human or snail host.

"Chronic infection with Schistosoma parasites makes life miserable for millions of people in tropical countries around the globe, and can lead to death," says NIAID Director Anthony S. Fauci, M.D. Anemia, fever, fatigue and other symptoms can make it difficult for sufferers to work or go to school, he adds. "New drugs and other interventions are badly needed to reduce the impact of a disease that lowers quality of life and slows economic development."

People become infected with Schistosoma when they wade or bathe in water inhabited by tiny snails that are the parasite's intermediate hosts. Microscopic fork-tailed parasites released into the water by the snails burrow into a bather's skin and travel to blood vessels that supply urinary and intestinal organs, including the liver, where they mature. Female worms, which live inside the thicker males, release many thousands of eggs each day. Eggs shed in urine and feces may make their way into snail-inhabited water, where they hatch to release parasites that seek out snails to begin the cycle again.

Schistosomiasis cases top 200 million every year, and some 20 million people are seriously disabled by severe anemia, chronic diarrhea, internal bleeding and organ damage caused by the worms and their eggs, or the immune system reactions they provoke. Though best known for causing chronic illness, schistosomiasis also kills: In sub-Saharan Africa alone it kills some 280,000 people each year.

Since the 1980s, the inexpensive anti-worm medication praziquantel has been administered to people in nationwide schistosomiasis control programs in dozens of tropical countries where the disease is common. While the drug is effective, it does not prevent a person from becoming re-infected through exposure to infested waters.

"The mass administration of a single drug increases the chance the parasites will become resistant to it," notes Martin John Rogers, Ph.D., a program officer in NIAID's Parasitology and International Programs branch. "Reliance on one drug is not a satisfactory long-term solution to the problem of schistosomiasis."

Finding new drug targets was a key goal of the team that sequenced the S. masoni genome. Led by NIAID grantee Najib M. El-Sayed, Ph.D., of University of Maryland, College Park, the group determined the sequence of 363 million nucleotides, encoding 11,809 genes. Analysis of the genes and the proteins they encode revealed the loss of some types of genes (and proteins) and expansion of other gene families relative to corresponding genes found in non-parasitic worms.

These genetic gains and losses are tied to the parasitic lifestyle of Schistosoma. For example, the researchers detected a large percentage of genes encoding proteases (enzymes that break down proteins.) Parasites, like Schistosoma, that must bore through skin and other tissues to invade their hosts require many such enzymes. Befitting a parasite that must navigate murky waters to find its intermediate host and later must travel through several tissue types in its human host, Schistosoma flatworms have sophisticated neurosensory systems that allow them to, for example, detect chemical, light and temperature levels in water or inside their hosts. Genes that encode signaling proteins involved in these neurosensory processes made up a significant proportion of both S. masoni and S. japonicum genomes.

The team responsible for the S. masoni genome also used bioinformatic computational techniques to translate genetic sequence information into maps of over 600 enzymatic reactions arrayed in multiple metabolic pathways. The analysis revealed 120 flatworm enzymes that could potentially be targeted with drugs that would disable the enzyme and inhibit the parasite's metabolism.

Finally, in an effort to find currently marketed drugs (such as protein or enzyme inhibitors) that might also be deployed against schistosomiasis, the researchers compared information about parasite proteins to a database of drugs directed at other human diseases. They found 66 instances of currently marketed drugs that might also be effective against schistosomiasis. "This list represents a good starting point, but, of course, more research is needed to determine whether any of the compounds could also be used to treat schistosomiasis," says Dr. Rogers.

NIAID provided major funding for the S. masoni genome sequencing. Additional support was provided by the Wellcome Trust of Great Britain and through grants from the Fogarty International Center and the National Institute of General Medical Sciences (both components of NIH.)

The S. japonicum genome was produced by an international team of researchers led by Zhu Chen, Ph.D., Ze-Guang Han, Ph.D., and Shengyue Wang, Ph.D., of the Chinese National Human Genome Center, Shanghai. NIAID grantee Zheng Feng, M.D., of the Chinese Center for Disease Control and Prevention, is a coauthor on the paper.