In an ambitious study of malaria, three groups of researchers have produced a detailed picture of the malaria parasites, including proteomic and gene-expression data, as well as sequence comparisons of four Plasmodium species.
The genome sequences generated by the project are available through GenBank, and the proteomic data and the microarray data are available through the international Plasmodium database called PlasmoDB (http://www.plasmodb.org).
The proteomic data will be particularly valuable to drug developers, because it allows them to identify which metabolic pathways are active in the parasite’s vertebrate-blood stages, and are therefore accessible to drugs, said Niel Hall, an assistant researcher at the Institute for Genomic Research.
Malaria parasites undergo three stages of their lifecycles in mosquitoes, three in mammalian hosts, and a sexual development stage as they are transferred from mosquito to mammal.
A research group from the Wellcome Trust Sanger Institute in the United Kingdom sequenced and annotated the genomes of two species of rodent Plasmodium, P. chabaudi and P. berghei, while scientists at TIGR compared these two sequences with those of P. yoelii, which had been sequenced already.
“From that analysis, we looked at how the genome of Plasmodium was evolving, and identified a lot of the genes which code for host-interacting molecules — the ones that are evolving most rapidly due to the arms race with the host immune system,” said Hall. These genes are most interesting to people working in vaccine discovery, he said.
The sequence of housekeeping genes was nearly identical to that of Plasmodium falciparum, the most harmful human parasite, said Hall.
The proteomic analysis was the first to look at the whole lifecycle of malaria parasites, with the exception of the “liver stage,” which is technically inaccessible in vivo in every species, Hall said. The group studied the proteome of the mosquito-resident stage using P. berghei, a rodent parasite, because P. falciparum is difficult to analyze during this stage. “Because a lot of the housekeeping genes are identical, we believe that you can directly take this data, and it should be applicable to Plasmodium falciparum as well,” said Hall.
The researchers have amassed enough proteomic data from P. berghei to complement the “half of the genome” about which there was no data in P. falciparum, said Hall. “It should be able to help people, whether they’re looking at vaccines or drugs, to be able to identify whether the target is expressed” in a particular lifecycle stage, he said.
Gene expression studies, carried out by researchers at the University of Leiden in the Netherlands and Imperial College in England, were directed toward identifying genes whose regulation coincides with a change in hosts from mammals to mosquitoes. The identified genes were up-regulated in the vertebrate host, while corresponding proteins were expressed later in the mosquito host.
“That’s going to be of use to people looking for transmission-blocking vaccines,” because these proteins can still be affected by components in the vertebrate’s blood after that blood has been taken as a meal by a mosquito, Hall said.
— CW