Parasite genome similarities offer hope for new drugs and vaccines
Authors: Stacie Bloom
Journal: Journal of Clinical Investigation (2005)

It took nearly 250 scientists from 47 institutions on 6 continents over 6 years to resolve the genetic makeup of 3 deadly parasites that are responsible for causing hundreds of thousands of cases of disease each year. The information, published in 3 papers in the July 15 issue of Science, provides new opportunities for developing new therapies (1–3).

“The most immediate benefit will be a change in the way research in these fields is conducted,” said Matthew Berriman, lead author on one of the papers. “With a genome sequence, there’s a framework for generating new ideas and rapidly testing them. The ultimate aim of these projects is to accelerate development of vaccines, new drugs, and diagnostics.”

African sleeping sickness, leishmaniasis, and Chagas disease are insect-borne diseases caused by the parasites Trypanosoma brucei, T. cruzi, and Leishmania major, respectively. Although incidences of these diseases are virtually unheard of in the US, they are endemic in sub-Saharan Africa, Central and South America, Brazil, India, and several other countries. Despite their prevalence, treatment options for these often-lethal diseases are suboptimal and expensive, and vaccines against the parasites have not been developed.

African sleeping sickness, transmitted by the tsetse fly, causes people to sleep for long periods during the day and leads to personality changes and seizures, which become progressively worse. Although 40,000 new cases are reported to the World Health Organization each year, the actual number of cases is probably much higher, since most cases are not reported at all.

Leishmaniasis, transmitted by the sand fly, can cause fever, swollen spleen, severe weight loss, and skin ulcers. The number of new cases of leishmaniasis each year in the world is about 2 million. Triatomine bugs spread Chagas disease, which is characterized by rash, diarrhea, cardiac problems, and enlargement of the esophagus or large bowel. According to the Centers for Disease Control (CDC), an estimated 50,000 of the 16 to 18 million people infected with Chagas disease will die each year.

“Thanks to these studies, scientists are much closer than they were 5 years ago to developing effective drugs against these terrible diseases,” said Najib El-Sayed, one of the principal investigators and a lead author on all 3 papers.

The critical finding was that each of the 3 pathogens shared the same 6,200 core genes, which exist in a similar order and represent 70% of the genes present, explained coauthor Peter Myler.

“This is surprising, considering the substantial differences the parasites display,” El-Sayed told the JCI. Each organism is transmitted by a different insect, infects a different set of tissues, has unique life cycle features, and causes very different symptoms and diseases.

“They also employ different immune evasion strategies,” El-Sayed explained. “L. major hides within the very same cells of the immune response and alters the function of the macrophages it infects, T. cruzi expresses a complex variety of surface antigens from within the cells it infects, while T. brucei remains extracellular but circumvents the host immune response by the periodic switching of its major surface protein.”

Nevertheless, the gene order and organization — called the synteny — along the parasite chromosomes is conserved. “This suggests that whole batches of genes are transcribed together and that regulating the activity of genes is very simple,” Berriman said. “If we can find an exploitable weakness amongst those common genes, we may be able to devise an intervention strategy that works on all 3 parasites.”

The genetic similarities uncovered among the parasites prevail over the differences, providing scientists with the opportunity to develop drugs to target all 3. On the other hand, detailed analysis of their variations could lead to targeted therapy against each parasite in particular.

A long-term goal for El-Sayed is to revitalize efforts to develop drugs against these neglected diseases. He is also sequencing the genome of Schistosoma mansoni, the causative agent of schistosomiasis, a disease caused by parasitic worms affecting 200 million worldwide.

“Genome sequences do not in themselves cure people,” El-Sayed said. “However, they do bring the prospect of safe and effective drugs, vaccines, and diagnostics nearer to fruition.”