The development of new drugs and vaccines against malaria poses one of the major challenges to current medical research. It must be grounded in the thorough understanding of the parasite's biology, including its interactions with the host, and the Anopheles mosquitoes that transmit it. P. berghei provides a highly tractable model to study the fundamental cell biology of malaria parasites and many aspects of their interactions with host and vector.
During the team's time at the Sanger Institue, we were particularly interested to learn how the cellular processes involved in sexual development and mosquito transmission are regulated through signal transduction pathways that control stage conversion, gene transcription and protein translation. To achieve this we often combined the global analysis of all other genes and proteins in the parasite cell with the targeted modification of one carefully chosen parasite gene. We also systematically analysed all parasite proteins for modifications that alter their function, such as the addition of phosphate or lipids.
Using these approaches we discovered a regulator of gene expression that functions as the master switch for the formation parasite stages in the blood that are essential to transmit Plasmodium to the mosquito (Sinha et al., 2014). We also found out that the same biochemical pathway regulates many different aspects of parasite biology by linking two intracellular messengers, calcium and a cyclic nucleotide (Brochet et al., 2014). We also showed how such discoveries can be exploited for drug development by demonstrating that a drug-like chemical inhibitor of a calcium dependent protein kinase can block malaria transmission to mosquitoes when administered to a mouse (Ojo et al., 2012).
The targeted modification of the genome is far more difficult in malaria parasites than in model organisms, such as yeast. To increase the rate at which discoveries can be made in P. berghei, we have developed protocols to produce more efficient genetic modification vectors and other molecular tools that allow researchers to rapidly switch parasite genes on and off. A production pipeline has now produced a genome scale set of gene knock out and tagging vectors for the P. berghei genome and pilot projects are well underway for other Plasmodium species. These resources are freely available to all researchers and can be viewed through the PlasmoGEM database. We also developed protocols to use PlasmoGEM vectors in genetic screens that query the functions of thousands of parasite genes at the same time. PlasmoGEM is a joint project with the Rayner group. It relies heavily on the reference genomes produced by Matt Berriman's Parasite Genomics team.