New possibilities from parasite bites

The genome of parasites which cause a devastating disease has shown scientists the way to developing new potential treatments.

By comparing three parasite species that cause the disease leishmaniasis, British researchers have identified a small number of genes that could provide the framework to target the search for new treatments.

Leishmaniasis is a crippling disease that affects about two million people every year in the UK, highlighting the need for new urgent treatments.

In their report, 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 8,000 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 - in contrast, in Plasmodium, which causes malaria, about 20 per cent of genes differ between related species.

High degree is genetic similarity

"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 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 per cent of Leishmania genes are lacking, so this comparative genome study provides a route to find those that might be essential to each species.

Around 350 million people in 88 countries on four continents are at risk of leishmaniasis and its incidence has risen sharply over the past ten years.

It is transmitted by the bite of various species of sandfly; wild and domesticated animals - as well as humans - act as a reservoir for the disease.

The study was published online in Nature Genetics on 17 June.

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