May 14, 2004 An essential switch in the life cycle of the malaria parasite has been uncovered by researchers in England, Germany and Holland.
They have established that to infect mosquitoes that transmit malaria, the parasites depend on a type of molecule normally found in plants, which they have named Calcium-Dependent Protein Kinase 4 (CDPK4).
The finding, based on studies of the malaria parasite of rodents, Plasmodium berghei, is described as basic science, but the authors suggest it may give drug researchers a specific and safe target against which to screen potential anti-malarial drug compounds.
The findings are reported in today's edition of the journal Cell (14 May) by researchers from Imperial College London, Leiden University Medical Center, Netherlands, and the Max-Planck Institute of Infection Biology, Germany.
"This work identifies the first signalling molecule that we know is essential for the transmission of the parasite," says Dr Oliver Billker, research fellow and lead author, from Imperial College London.
"It is an essential molecule because if the malaria parasite doesn't have this gene function then transmission of the parasite to mosquitoes is completely disrupted. It is also specific to development of the male gametes only."
"CDPK4 is unusual because apart from the malaria parasite and some other single-celled organisms, it is only seen in plants. This makes it appealing as a target for drug developers, who would not run such a big risk of developing a drug with strong side effects, because CDPK4-like molecules do not exist in humans."
The human malaria parasite has two hosts, humans and mosquitoes. Just after the mosquito has taken a blood meal from a human, malaria parasites in the mosquito bloodstream differentiate into male and female sexual forms, named micro- and macro-gametes respectively.
In 1997, Imperial College researchers discovered that the mosquito molecule xanthurenic acid is responsible for inducing development of the malaria parasite at this stage. Since then further work has shown that xanthurenic acid specifically causes a rise in calcium levels within the parasite.
Understanding how this calcium signal, which is ubiquitous in cells, is translated into a specific action in the cell at a specific stage of the parasite life cycle, took two years of careful scientific detective work by Dr Billker and colleagues.
Using data from the malaria parasite genome project completed in 2002, the researchers uncovered six protein kinases with striking similarities to those from a family normally seen in plants. These plant-like molecular switches have a unique architecture and, unlike their human counterparts, are regulated by calcium directly.
By constructing transgenic parasites in which individual kinases were deleted from the genome, the team established the essential role played by one, which they named CDPK4.
"This is an example of how we exploit genome data now," says Dr Billker. "We combine them with new methods of functional analysis such as microarrays, which tell us what genes are active at specific stages of the parasite's life cycle, and they are giving us great insights into the molecular components involved in signalling and regulation of the parasite." "We will use this method in future to dissect out more signalling pathways involved in the malaria parasite's life cycle. To a cell biologist it is very exciting to see such a well-defined trigger of parasite differentiation," adds Dr Billker.
The research was supported by the UK Medical Research Council.
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