In an innovative project with implications for malaria vaccine development, scientists have used genomics, proteomics and gene expression studies to trace how malaria parasites evolve on a molecular level as they move between their hosts and insect vectors.
That unprecedented focus on the parasites’ complex life cycle is helping researchers understand when different genes switch on and off as the pathogens metamorphose through seven different life stages. In turn, that molecular-level data will benefit biomedical scientists who are identifying new targets for vaccines that would impede the parasite during stages when it is particularly vulnerable to intervention.
“We hope this project will help vaccine researchers find the best targets against malaria,” says scientist Neil Hall, the first author of the paper that appears in the January 7th issue of Science. “The study’s findings will help scientists identify parasite genes that are interacting with the host as well as new gene targets for vaccines that aim to prevent parasite transmission in the mosquito.”
The study highlights the genes in four malarial species that evolve rapidly because of “selective pressures” in the stages of their life cycles in their mosquito vectors and in their mammalian hosts. Malaria parasites undergo three stages in their mosquito vectors, three stages in their vertebrate hosts and a sexual development stage during which the parasite is transmitted between vector and host.
The Science paper represents the culmination of four years of cooperative work by scientists at several research institutes, including: the Wellcome Trust Sanger Institute in the U.K., where the sequencing and genome annotation was performed on two species of rodent malaria (Plasmodium chabaudi and P. berghei); the University of Leiden in the Netherlands and Imperial College in England, where scientists carried out gene expression studies; and The Institute for Genomic Research (TIGR), in Maryland, where scientists did a comparative analysis of the two draft genomes with those of the first rodent malaria parasite to be sequenced, Plasmodium yoelii.
The first author of the paper is Hall, a TIGR Assistant Investigator who did most of his work on this project while in his previous position as a bioinformatics scientist at Sanger. He was also the first author of the 2002 study – led by scientists at TIGR, Sanger, and Stanford University – that presented the complete genome of Plasmodium falciparum, the deadliest human malarial parasite.
Hall says the Science paper is important because:
* The study takes an “evolutionary approach” to exploring how the Plasmodium genome has evolved. By comparing four sequenced genomes (the human malaria P. falciparum and the rodent malarias P. yoelii, P. chabaudi and P. berghei), the scientists found that the major differences between the malarial species are found in the virulence factors (which are at the chromosome ends) while the “housekeeping” genes are almost totally unchanged.
* Researchers showed that the parasite genes evolve most rapidly when they are expressed in the mammal hosts (human/mouse). That may represent a mechanism by the parasites to repulse the attack of the host’s immune system.
* For the first time, scientists were able to study the protein expression of the parasite in the mosquito vector. Researchers hope this will shed light on how the mosquito and parasite interact, and perhaps will lead to new ways of controlling the parasite in the vector.
* Hall and Leiden scientists identified evidence of an unusual method of gene regulation (called post transcriptional regulation) at the transition between the vertebrate host and the mosquito. That motif regulates proteins that are switched on as the parasite enters the mosquito.
Hall’s group identified the gene regulation by comparing the genes expressed in the sexual stage transcriptome with the proteomes of both the sexual stage and a developmental stage in the mosquito. Several genes were identified for which transcripts were detected in the sexual stage but with protein products specific to the mosquito stage, indicating delayed translation of transcripts from these genes.
Hall says that gene-regulation motif “is particularly interesting because these proteins, expressed early in the mosquito, are the target of transmission-blocking vaccines" – that is, vaccines which raise antibodies that attack the parasite in the vector. (Such antibodies are in the “blood meal” and still work for an hour or so after the mosquito bites).
Another TIGR scientist who played an important role in the project is Associate Investigator Jane Carlton, who had led the sequencing of P. yoelii at TIGR and who has worked on Plasmodium for most of her research career. While at the University of Florida, Carlton had led the first large-scale gene identification project in P. berghi – including information that was used by Leiden University researchers in their investigation of genes that are turned on during the parasite’s reproduction stage.
At TIGR, Carlton constructed a composite of all three rodent genome sequences (P. yoelii, P. berghei, P. chabaudi) by aligning them against the P. falciparum genome to create a whole-genome synteny map of the four species. TIGR scientist Shelby Bidwell helped in the generation of the synteny map. In collaboration with Leiden University researchers, they were then able to generate maps that compare the degrees of similarity among genes on P. falciparum chromosomes and its rodent-malaria counterparts.
“The paper is significant on many levels, including the integration of draft genome sequence data with microarray and protein expression data,” says Carlton. “This project also shows the power of collaboration between international institutes with different areas of expertise. It was remarkably productive collaboration.”
The Plasmodium study was sponsored by The Wellcome Trust, the European Union’s research directorate, and the U.S. National Institutes of Health.
The Institute for Genomic Research (TIGR) is a not-for-profit research institute based in Rockville, Maryland. TIGR, which sequenced the first complete genome of a free-living organism in 1995, has been at the forefront of the genomic revolution since the institute was founded in 1992. TIGR conducts research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes.
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