Genome studies may help target new drugs to fight them

Jul 18 2005

One parasite causes a deadly sleeping sickness in Africa. The second damages the internal organs of millions of Latin Americans. The third causes terrible lesions on the face or limbs of victims from Brazil to India.

The three parasites - the culprits behind African sleeping sickness, Chagas disease and leishmaniasis - cause markedly varying diseases and are carried by different insect vectors. But scientists have found that the pathogens have a core of about 6,200 conserved genes. Their genetic similarities far outweigh their differences.

"This common core of genes is extremely important because it may provide targets for a new generation of drugs that might fight all three parasites, which threaten millions of people worldwide," says Najib El-Sayed, the first author of two of the parasite papers that appear in the July 15 issue of Science and senior author of a third paper. "At the moment, there are no vaccines and only a few inadequate drugs to fight these devastating and neglected diseases."

El-Sayed is a molecular biologist at The Institute for Genomic Research (TIGR), of Rockville, Maryland, which conducted the genome sequencing and analysis along with scientists at the Wellcome Trust Sanger Institute in Hinxton, U.K.; the Seattle Biomedical Research Institute (SBRI); and the Karolinska Institutet, in Stockholm, Sweden.

The Science issue includes several papers, including genome studies of Trypanosoma cruzi, which causes Chagas disease; Trypanosoma brucei, which causes African trypanosomiasis, also known as sleeping sickness; and Leishmania major, which causes the skin disease leishmaniasis and an internal disease known as kala azar. Another paper compares the three related genomes.

By determining the shared genes and focusing on those that differ, the comparative study sheds new light on the genetic basis for the differences between the parasites - including how they infect people, how they cause human disease, and why they are carried by different insects. (T. cruzi is carried by blood-sucking triatomine insects; T. brucei by the tsetse flies; and L. major by sand flies.)

The comparison found dozens of genes found in all three parasites that may have been acquired from bacteria through lateral gene transfer. In addition, studies of the parasites' Variant Surface Glycoproteins (VSGs) found T. brucei to have the most complex genetic apparatus for avoiding host immune systems and, at the same time, to be the most dependent of the parasites on the host's metabolism. Scientists also discovered that many of the genes specific to each species are found in so-called sub-telomeric regions near the ends of chromosomes - areas where the genome tends to be more changeable.

An important finding in the T. cruzi genome study was the discovery of a novel and large set of 1,300 genes (called the "mucin-associated surface protein," or MASP, genes) that may play a role in the parasite's evasion of the human immune system or in its ability to survive in the variety of hosts that it infects.

The T. cruzi project was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health. The major funders of the T. brucei and L. major genome projects were The Wellcome Trust and the NIAID.

Matthew Berriman of Sanger, the first author of the T. brucei genome paper, predicts that the genome sequences will help advance research into diseases that have been "neglected" in the past. "Genome sequences allow ideas to be tested and more quickly turned into reality," Berriman says. "The basic building blocks of all three parasites are now known."

Peter J. Myler of SBRI, who shared the first authorship with El-Sayed on two of the papers, says: "Now that the genes of these parasites are mapped out, it's much easier to identify genes that are critical for parasite survival. Genes encoding proteins that are involved in critical biological processes often serve as drug targets."

Much of the world's population in tropical and sub-tropical areas is at risk of contracting one or more of the diseases. Chagas disease - which may have infected Charles Darwin - infects as many as 18 million people and threatens about 100 million others in Latin America, according to the World Health Organization. African sleeping sickness (trypanosomiasis) infects between 300,000 and 500,000 persons and threatens more than 60 million people in 36 countries in sub-Saharan Africa. Leishmaniasis (which also can be caused by related parasites) is endemic in 88 countries and may threaten as many as 300 million people.

The Institute for Genomic Research (TIGR), which sequenced the first complete genome of a free-living organism in 1995, is a not-for-profit research institute based in Rockville, Maryland. TIGR conducts research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes.