Portland, Ore.

Landfear lab assists effort seeking targeted drugs for deadly parasite, others like it

An Oregon Health & Science University researcher is among an international team of scientists that uncovered the genomes of three deadly parasites infecting millions of people primarily in Third World countries.

Scott Landfear, Ph.D., professor of molecular microbiology and immunology in the OHSU School of Medicine, co-authored one of three studies appearing today in a special edition of the journal Science that explored the genome sequences of so-called Tritryp parasites: Trypanosoma brucei, Trypanosoma cruzi and Leishmania major.

By sequencing the parasites' genomes, scientists hope to identify the genetic pathways through which their cells communicate and grow, creating more targeted drugs that attack the parasites and reduce their resistance to these therapies.

While Landfear's laboratory examined all three organisms as part of the Tritryp genome sequencing effort, his paper focused on Trypanosoma brucei, the organism that causes African trypanosomiasis, or sleeping sickness, which affects between 300,000 and 500,000 people in 36 countries. Spread by tsetse flies that are endemic in the region, it often is fatal because many people go untreated.

The Trypanosoma brucei team found the parasite's genome contains a total of 9,068 genes, including nearly 800 genes used by the parasite to evade the human immune system.

Trypanosoma cruzi, spread by reduviid or "kissing" bugs, is the version of trypanosomiasis that occurs in Central and South America. It causes Chagas disease, which infects 16 million to 18 million people in 21 countries, according to the World Health Organization. Leishmania major causes leishmaniasis that takes three forms: kala azar, espundia and cutaneous leishmaniasis, which together affect more than 12 million people worldwide, primarily in Bangladesh, Brazil, India, Nepal and Sudan.

Landfear's lab identified nearly 20 families of metabolic proteins responsible for transporting nutrients and waste products through the membranes of the parasites' cells. They include transporters for amino acids, water, metals, calcium, potassium, sodium, and sugars such as glucose.

"My lab works on membrane transporter proteins that are responsible for bringing in a whole variety of nutrients parasites require to survive," Landfear said. "All of the parasites express hundreds of different transport proteins and you want to know what families of transporters are there and how they may differ from the human host."

The discovery followed about three weeks of work, with help from bioinformatics experts in Cambridge, United Kingdom, to pinpoint the genes in the parasites likely responsible for membrane transporting, Landfear said. The list of original candidates was 500 pages long.

"You weed out a lot of stuff that has nothing to do with transport to try to be as comprehensive as possible," Landfear added. "So I came up with a list of all the genes encoding transporters, then did a comparative analysis between the different species."

Landfear found, among other things, that one parasite may contain transporters that the other two don't. And one of the most striking discoveries was that the parasites' cells contain few transcription factors, which are proteins responsible for regulating gene function.

"Most organisms have a large battery of proteins that are called transcription factors that regulate a variety of genes," Landfear said. "These three organisms have very few transcription factors, and that says something fundamental about how they express their genes."

The discovery of the Tritryp genomes may have much wider, long-term implications than potentially reducing or eliminating the epidemics caused by the parasites.

"These organisms have given us insights into other ways organisms can function, particularly in the way they can express and control expression of their genetic material," Landfear said. "There's a lesson there in biology."

The Trypanosoma brucei study was funded by the Burroughs Wellcome Fund, Wellcome Trust, the National Institutes of Health, the European Union and the World Health Organization.