Parasite Genome Sequences Offer Hope for New Drugs and Vaccines, Science Studies Say
Micrograph of a rat blood smear revealing Trypanosoma brucei parasites using a Giemsa stain technique. Image courtesy of CDC/Dr. Mae Melvin
Scientists have sequenced and compared the genomes of three of the parasites responsible for sleeping sickness, Chagas disease and leishmaniasis, three devastating diseases of the developing world.
These parasites collectively cause disease and death in millions of humans each year, and the new genome sequences provide critical information for drug and vaccine developers, according to new research appearing in the 15 July 2005 issue of the journal Science.
In addition to offering drug and vaccine leads, the research provides a detailed roadmap of the biology and evolution of these unicellular organisms, or "protozoa," from the family Trypanosomatidae, which parasitize humans and other mammals, birds, reptiles, fish, insects and plants. Insects transmit these disease-causing parasites to humans living in tropical and subtropical regions of the world.
Researchers identified about 6,200 core genes that are present in all three parasites in a similar order within each genome. Some of the proteins encoded in these genes could serve as targets for drugs that would be effective against all three parasites, a worthy goal given the fact that there are currently no vaccines for these diseases, and only a few drugs, most of which are inadequate due to resistance, toxicity or expense.
The sequencing initiative also identified genes specific to each parasite and this information could be useful for parasite-specific drug and vaccine development efforts.
"Thanks to these studies, scientists are now much closer than they were five years ago to developing effective drugs against these terrible diseases," said Science author Najib M. El-Sayed, Assistant Investigator from The Institute for Genomic Research in Rockville, Md.
"These are neglected diseases. The average person in the developed world has not heard of them, but they are absolutely devastating across the developing world," said Science author Matthew Berriman, Senior Computer Biologist from Wellcome Trust Sanger Institute in Hinxton, United Kingdom.
While the three pathogens share many general characteristics, each is transmitted by a different insect, displays unique life cycle features, infects different tissues, evades immune systems in unique ways, and causes different diseases in the humans and the other organisms they infect. All three diseases can lead to severe sickness or death if patients do not receive early treatment.
The 15 July 2005 issue of Science includes a trio of research articles, each primarily focused one of the parasites, a comparative research article, two related research reports, a "Viewpoint" article and an editorial.
"The original goal of the three genome projects, which were initiated independently, was to decode the genetic blueprint and gain insights into the biology of each of the three parasites. The comparative study is a valuable outgrowth of those projects which has yielded important results," said El-Sayed.
Trypanosoma brucei causes sleeping sickness, also known as Human African trypanosomiasis, and is spread to humans by the notorious tsetse fly. The disease's greatest impact is in Sub-Saharan Africa. Fevers, headaches, joint pains and itching characterize the first phase of the disease. When the parasites cross the blood-brain barrier and enter the central nervous system, they disturb the sleep cycle and other neurological processes.
Trypanosoma cruzi causes Chagas disease. Blood-sucking triatomine bugs, with many different common names including "assassin bugs," live in the cracks and crevices of poor-quality houses in Central and South America and transmit the parasites to humans. People infected with T. cruzi often suffer cardiac, gastrointestinal or neurological damage after decades of persistent infection without disease symptoms.
Leishmania species cause a spectrum of human diseases in Central and South America, southern Europe, Asia, the Middle East and Africa and are transmitted by tiny sand flies. The researchers sequenced the genome of Leishmania major, one of the Leishmania parasites responsible for a skin disease causing sores that often leave disfiguring scars. L. major serves as a model for other Leishmania species, including those causing the internal or "visceral" disease resulting in fever, weight loss and an enlarged spleen and liver and sometimes death.
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, said Science author Peter Myler, Scientist at the Seattle Biomedical Research Institute and Research Associate Professor at the University of Washington.
The researchers found many genes coding for enzymes not known in humans. For example, the genome project turned up dozens of core genes shared by the three parasites that were probably acquired from bacteria through a process of "horizontal gene transfer." Drugs that hit these acquired enzymes could be fruitful drug targets because they are less likely to affect the host.
Another drug development approach is to focus on proteins that are unique to individual parasites. Many of these species-specific genes are located at the ends of the chromosomes and may encode proteins the parasite needs to survive or cause disease in humans or other host animals. Genes involved in parasite-specific adaptations are unlikely to be shared by their human hosts, making them even more attractive as drug targets.
"Because of their distinct evolution, trypanosomes present a plethora of potential drug targets, and potential drugs are almost certainly languishing in the chemical libraries of pharmaceutical companies," writes George Cross from Rockefeller University in New York, NY. in this week's Science editorial.
Comparing the three genomes also highlights differences in metabolic capabilities of the parasites that reflect the diversity within their lifestyles and correlate with differences in their hosts and vectors. T. brucei has the least overall metabolic capability and L. major has the greatest. The sand flies' ability to feed on nectar may allow L. major to have a more complex sugar metabolism.
In the hopes of developing a T. cruzi vaccine, Science author Rick Tarleton, Research Professor from the University of Georgia in Athens, Ga. and colleagues pieced together which proteins are present within the parasites while they are infecting humans.
"We identified proteins that would make good T. cruzi vaccine candidates and deserve further testing," explained Tarleton.
Lots of unexpected information fell out of this "proteome" analysis, especially related to how T. cruzi obtains energy. Some of these new insights are applicable to drug and vaccine design and others are, at this point, just interesting biology, said Tarleton.
The sequencing of the L. major genome marks an important step toward understanding the genetic differences that make other Leishmania species more dangerous – information critical for efforts to develop a vaccine effective against a broad range of Leishmania species, according to Myler.
Developing vaccines for T. brucei appears less promising because these parasites are so good at escaping the immune system. The new research provides a better look at the vast arsenal of dormant genes thought to help T. brucei in their role as escape artists.
In a paper in the same issue of Science, David Pérez-Morga and colleagues report the mechanism by which a protein found in the serum of humans called "apoL-I" kills African trypanosomes, the parasite responsible for sleeping sickness.
In a "Viewpoint" article, Carlos Morel and colleagues highlight the growing ability of some developing countries to undertake health innovation with their own energies and resources. For example, the majority of the short strands of DNA used to identify the genes of all three parasites were sequenced at institutions in Africa and South America.
Daniel B. Kane
17 July 2005