A comparison of three parasite species that cause Leishmaniasis has identified a small number of genes, many new to biology, that will provide a framework to target the search for new treatments.
Leishmaniasis is a devastating disease that affects about two million people each year and threatens one-fifth of the world's population and new treatments are desperately needed.
In their report in Nature Genetics, published online on Sunday 17 June 2007, the researchers compared the genomes of L. infantum and L. braziliensis, which cause life-threatening visceral and disfiguring mucocutaneous leishmaniasis, respectively, with the sequence they produced in 2005 for L. major, which causes a less severe, cutaneous form of the disease. Despite the major differences in disease type, only 200 out of more than 8000 genes present in each genome were found to be differentially distributed between the three species. This exceptionally small variation in gene content has given new insights into those processes that may determine disease severity in humans.
"Identifying factors that allow three closely related organisms to cause vastly different clinical outcomes is a major quest for researchers and in this study we have narrowed the search to a number that can be realistically studied," commented Dr Matt Berriman, senior author on the paper, from the Wellcome Trust Sanger Institute.
The researchers found only five genes in the L. major genome for which no trace could be found in the other two species. By contrast, in Plasmodium, which causes malaria, about 20% of genes differ between related species.
"Clearly there must have been considerable evolutionary pressure over time to maintain the structure and sequence of the Leishmania genomes - the degree of similarity between these species was unexpected," explained Professor Deborah Smith, collaborator on this project at the University of York. "Perhaps only a few parasite genes are important in determining which type of disease develops after infection and the host genome plays a major role in clinical outcome."
The results picked up another surprising finding: the team could assign a function to only one-third of the 200 genes restricted to one or two of the species.
"The genome sequences have given us a short-cut to a small number of largely novel genes," explained Dr Chris Peacock, first author on the report. "Given their lack of similarity to human genes, they present a limited repertoire of potential targets for drug and vaccine development allowing researchers to optimise the use of limited resources."
Leishmaniasis is one of the neglected diseases that desperately need new research, as WHO/TDR notes: "Treatment of visceral leishmanisis by first-line drugs is long (4 weeks), given systemically, and expensive (US$120-150)". The affordable drugs have been in use for more than half a century and drug resistance is rife, creating a desperate need for new treatments. Biological studies for the function of 50% of Leishmania genes are lacking, so this comparative genome study provides a route to find those that might be essential to each species.
One potential target is the CFAS gene that codes for cyclopropane fatty acid synthase, an enzyme that may be involved in producing components of the cell membrane. CFAS is present in the genomes of L. braziliensis and L. infantum, but is absent from the human genome. The parasite genes are thought to have been acquired from bacterial species that have very similar sequences.