Comparative transcription analysis to identify novel targets for malaria intervention.

Despite extensive efforts to control the parasite, malaria remains one of the most important health burdens in the world. Genomic, transcriptomic as well as proteomic approaches are powerful tools to study the biology of the parasite and the availability of the genome sequences of now six different species of Plasmodium have significantly improved our understanding of parasite biology. Despite this our understanding of parasite induced pathology, mechanisms of immune evasion and adaptation, as well as mechanisms of drug resistance remains limited. Information to improve our understanding of any of these phenomena would be not only valuable in terms of understanding parasite biology but would also be useful for the management of clinical cases and the development of new diagnostic tools. The genomes of Plasmodium species code for approximately 5,000 to 6,000 genes. For about half of them there are no corresponding orthologues in any other organism making functional annotation difficult. The fact that these genes are either unique to the parasite or have diverged so much from their corresponding gene in other organisms makes them attractive drug targets. In the proposal we will use comparative transcriptomics to investigate transcriptional differences in parasites as they relate to disease severity, immune evasion and host adaptation as well as drug resistance. The transcriptional difference will provide important insights on the factors that regulate these processes in the parasite. In parallel we will utilize the transcriptome data to further improve the interaction network that we have generated. This improved network will further improve our ability to functionally annotate parasite unique genes. Finally unique genes predicted by the different approaches to play an important role in the parasite will be functionally characterized. Combining the transcriptional analysis with functional validation provides new insights into parasite biology as well as providing a list of unique drug targets.