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US/African project deciphers deadly parasite genome

An innovative North-South research collaboration has culminated in a study published in this week's Science that provides molecular clues to help develop new ways to treat or prevent East Coast fever.

The disease, which kills a million cattle a year in East and Central Africa, has had a devastating impact on rural areas ?such as Maasai tribal communities in Kenya ?where cattle play a crucial role in the local society and economies. The fever is caused by the parasite Theileria parva, whose genome is analyzed in the Science paper.

The study results from an unusual five-year research collaboration between two leading U.S. and African laboratories ?The Institute for Genomic Research (TIGR) of Rockville, Maryland, and the International Livestock Research Institute (ILRI) of Nairobi, Kenya.

That innovative U.S./African partnership has enriched the quality of African scientific research while also helping researchers better understand the parasite and the disease it causes. In addition, the unusual biology of the parasite is shedding light into aspects of human cancer biology.

TIGR's president, Claire M. Fraser, says the project shows how North-South research collaborations can be effective and can benefit scientific partners on all sides. "This unique partnership has given a boost to the goal of developing a vaccine against a disease that has had a severe impact on so many East African communities," Fraser says.

Carlos Seré, the director-general of ILRI, says that mapping the T. parva genome represents a significant step toward the ambitious goal of developing a genomics based sub-unit vaccine to control this protozoan pathogen. "Such an achievement would be a major breakthrough for vaccine development and would increase the hope for tackling other protozoan diseases," he says.

East Coast fever, which is endemic in several African countries, was first recognized about a century ago as a parasitic disease. The disease became a major concern after it was introduced into South Africa in the late 1890s when infected cattle from northern Rhodesia (now Zambia) were imported to replace thousands of animals that had been killed during a devastating outbreak of rinderpest.

Nobel Prize winning German microbiologist Robert Koch, who had been sent to east Africa to study the disease, was the first to describe the T. parva parasite and made the first attempt to develop a vaccine. Veterinary bacteriologist Arnold Theiler later made significant discoveries about the parasite, which is named for him.

Vish Nene, a former ILRI scientist who came to TIGR in 2001 to join the T. parva project, says the genome sequence provides useful information that will help scientists better understand how the parasite malignantly transforms cattle white blood cells into cancer-like cells that multiply rapidly, eventually leading to fever and death. By studying that process, scientists are trying to learn more about the genesis of human cancers.

"This parasite has an astonishing ability to induce cancer in its host cell in a way that is reversible," says Nene. "There are clear links to cancer biology in humans, and this study has given us some clues to pursue."

The genome is also helping scientists who study human malaria, which is carried by a related parasite. Malcolm Gardner, a TIGR scientist who is the paper's first author, says scientists found that T. parva "lacks several biochemical pathways that are present in the malaria parasite, suggesting that Theileria is more dependent on its host for nutrients."

Gardner, who was also the first author of the 2002 paper on the genome of the deadliest human malaria parasite, says that several of the malaria parasite's metabolic pathways that Theileria lacks are found in an intracellular structure called the apicoplast. "This information could be used to develop drugs that could be targeted specifically at each parasite or at several re lated parasites," he says.

TIGR determined the genome sequence of T. parva and shared in the annotation of the genome ?the identification of genes and the assignment of gene functions ?with scientists at ILRI. Much of the annotation of the T. parva genome was performed by two bioinformatics specialists at ILRI.

"ILRI's involvement in the genome project supported the establishment of its bioinformatics unit," says Richard Bishop, the lead ILRI scientist on the genome project. The ILRI bioinformatics unit will in turn support the wider application of bioinformatics through the Biosciences east and central Africa (BecA) initiative, which is part of the New Partnership for Africa's Development (NEPAD) continental science and technology network. These skills will be crucial to help African institutions understand and exploit genomic data for product development.

The T. parva project was funded by the TIGR Board of Trustees; ILRI; prize money donated by TIGR's chairman, J. Craig Venter; and the United Kingdom's Department for International Development. Additional contributions came from the Rockefeller Foundation and the U.S. Agency for International Development.

The TIGR/ILRI study was published in Science along with a parallel report on the genome of the related cattle parasite T. annulata, which causes tropical theileriosis in cattle and transforms macrophages, monocytes and B-lymphocytes. That study was led by scientists at the Wellcome Trust Sanger Institute in Hinxton, UK.

The lead author of Sanger's T. annulata genome manuscript, Arnab Pain, says that "a major focus of our analysis was to identify the key weapons in the parasite's genetic armory that it could use to trigger and maintain the cancerous state of the infected host cell."



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