BioWorld International Correspondent
LONDON It may one day be possible to protect both humans and mosquitoes from the malaria parasite with the same vaccine, a recent discovery suggests. Scientists working in England and France have found that proteins belonging to the same family of genes help the malaria parasite infect both human blood and liver cells and the cells of the mosquito.
The same team has shown that Plasmodium yoelii yoelii, a form of malaria that infects mice, is able to switch manufacture of the different proteins very precisely when it reaches a new host or a new type of cell.
Development of a vaccine using the new strategy is likely to take many years, however. Peter Preiser, senior scientist in the division of parasitology at the National Institute of Medical Research in London, warned that much more work needs to be carried out first to identify the conserved regions of the numerous proteins concerned.
He told BioWorld International that although information about the genome sequence of the Plasmodium species is now becoming available, much of the information is in a raw state and requires much further analysis before all the different genes can be identified. “Even identifying the conserved regions within these proteins we know are responsible is going to be a major task, because each is 235 kilodaltons in size more the size of an encyclopedia than of a small paperback,” he said.
Preiser, together with colleagues at the National Institute of Medical Research and collaborators in Paris, has published the results of the study in a paper in the Jan. 11, 2001, Science titled: “Stage-Specific Transcription of Distinct Repertoires of a Multigene Family During Plasmodium Life Cycle.”
The various malaria parasites have a complex life cycle. The parasite is transmitted to its vertebrate host, such as a human, by the bite of an infected mosquito, which injects a form of the parasite called a sporozoite. These migrate in the blood to the liver, where the parasite invades liver cells and replicates, eventually releasing thousands of liver merozoites into the bloodstream. These invade red blood cells, multiplying and eventually releasing blood merozoites, which repeat the cycle of infecting red blood cells.
When another mosquito bites the infected person, that insect becomes infected. The parasite invades its mid-gut, developing into a form called an ookinete. The ookinete then invades the mosquito gut lining and develops into an oocyst, which produces hundreds of sporozoites that migrate to the salivary glands, ready to be injected when the mosquito next takes a blood meal.
“What we were interested in,” Preiser said, “is the mechanism of how the malaria parasite gets into a cell. In terms of an intervention strategy, this is a really important target because if you can stop the parasite from getting into the liver cell, the red blood cell or even the mid-gut cell of the mosquito, it will die.”
Studies carried out by Preiser and colleagues in London, together with his collaborators Laurent R nia at the Institut Cochin, Irene Landau at the Mus um National d’Histoire Naturelle and Georges Snounou at the Institut Pasteur, all in Paris, have begun to answer this question. The proteins involved are encoded by a multigene family a group of genes scattered throughout the genome that are very similar but not identical. In P. y. yoelii, there are 35 such genes in this multigene family.
“These proteins, which are called the Py235 family, act like the key that allows the parasite to get into a cell, and provide different keys for the different locks on cells whether because the cells are of different types, or because they are from different hosts,” Preiser said.
Earlier work by the team already had shown that when the parasite invades the red blood cells, it makes merozoites that express a different member of the gene family to that of the infecting liver merozoite, presumably to ensure that whatever “key” is required is available.
But Preiser and his colleagues realized that there are many other occasions when the parasite has to invade cells to continue its life cycle, and wondered whether any of the same genes and proteins were involved at these times. He said: “We felt quite confident that the liver merozoites, when released from the liver, would express one of these proteins because they also infect red blood cells. But to our surprise, we found that the sporozoite also expresses a Py235 protein, and that we could inhibit its ability to get into liver cells by using specific antibodies against the protein.”
Further investigations showed that the proteins expressed by the sporozoites, by the merozoites in the liver, and by the merozoites in the bloodstream were different members of the Py235 family and did not overlap in any way.
Additional studies by the team will focus on which promoters are active during which parts of the parasite’s life cycle. “We also want to establish the proof of principle that it is possible to develop a vaccination approach that would affect all different stages of the life cycle,” Preiser said. “First we will need to identify all the highly conserved motifs that are found in the proteins expressed in the blood stages and the sporozoite stages.”