Using models to understand malaria

Malaria is one of the world's major killers. More than 500 million people live in epidemic regions and some 2 million - mostly children - die each year. And each year, drug resistance increases in the malarial parasite, Plasmodium falciparum, and the search for new treatments becomes more desperate.

New research by a consortium of researchers, published Friday 7 January 2004 in Science magazine, provides new clues to understanding and attacking this scourge. The team looked at all of the genes in four different species of Plasmodium, the human pathogen and three species used to model the disease. The results reveal an amazingly complex and subtle guide to surviving and prospering in a host.

Looking at four species together, has allowed the researchers to look at which genes vary the most. Genes for core functions - the essential steps of life - are shared between species and are located in the centres of the chromosomes. Genes causing the differences - and differences are crucial in the search for new treatments - lay in regions towards the ends of chromosome and are related to cell surface variation, escape from the host immune system, and invading the host's cells - where the parasite thrives.

This comprehensive four-year study involved researchers at the Wellcome Trust Sanger Institute, the University of Leiden, Netherlands, Imperial College, London, UK, The Institute for Genomic Research (TIGR), Maryland, US and the University of Glasgow.

The results suggest that proteins that decorate the Plasmodium cell surface - those that would be attacked by the host immune system - are under pressure to diverge in order to escape detection. Amongst these variable genes are large families, with sometimes hundreds of members.

One family is the Plasmodium interspersed repeat genes (PIR), which account for between 2 and 15% of all Plasmodium genes. Because different sets of PIR genes are detected in parasite isolates obtained from different patients, there are thought to help the parasite evade the immune system.

Malaria has a complex life cycle, appearing in seven different forms in the mammalian host and the mosquito vector. Genes and proteins specific to these stages may be key to parasite development and hence potential new targets for vaccines or medicines.

In the search of the parasite genomes, a novel DNA sequence 'signature' was found to be associated with genes are used as the parasite moves from human to mosquito host. This could be an important tool in the search for further genes involved in this vital part of the life cycle that is extremely difficult to study, even with existing models. Ultimately it is hoped that this signature will lead us to new candidates for vaccines that block malaria transmission.

Proteins encoded by 2000 of the approximately 5000 genes in the Plasmodium genome were detected at different stages in the parasite's life cycle. About 10% of these were found throughout the life cycle. However, nearly half of those studied - or 20% of the parasite's capacity - were found at stages associated with the parasite's invasion of blood and liver cells and my offer promise in the search for drug and vaccine discovery.

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