Functional genomic tools for in vivo study of P. vivax

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DESCRIPTION (provided by applicant): Efforts to eradicate malaria will depend on having effective therapies that can eliminate Plasmodium vivax. At present the only licensed antimalarial that can accomplish the elimination of the latent form of the parasite, the hypnozoites, is primaquine, which has liabilities in terms of likely widespread parasite resistance or tolerance, and toxicity to individuals with glucose 6 phosphate deficiency. There is also currently no licensed vaccine for P. vivax malaria. Efforts to study the mechanisms of drug resistance in P. vivax, to develop novel drugs or to discover new vaccine antigens are complicated by the fact that the parasite cannot be easily cultured, making it difficult to phenotype parasites, characterize genes or test hypotheses using molecular methods such as allelic exchange or transient transfection. Because of these difficulties genome-dependent methods offer one of the most efficient ways to determine what genes are doing, when they may be active in the parasite, how they are regulated, which genes may be interacting with the immune system, and which are under selective pressure from the host immune system or from drugs. As has been shown in P. falciparum descriptions of when genes are transcribed, and whether or not they are amplified or variable provides a foundation for a variety of drug and vaccine discovery research projects. For example copy number variants may be detected within the genome and genes whose activity levels are regulated by dosage compensation may prove to be interesting novel drug targets. Genes which are highly transcribed in the salivary gland sporozoite and which exhibit signatures of immune selection, such as CelTos, may encode new candidate antigens for preerythrocytic vaccines. This is an exploratory project that seeks to test the hypothesis that the same genome-dependent methods that have been used successfully with cultured P. falciparum can be used on P. vivax parasites that have been obtained directly from infected patients. If successful the work will establish a molecular toolbox that can be used by researchers working on field isolates of P. vivax and provide baseline transcription and variability data that may be useful to those making decisions about vaccine candidates, studying populations, relapse rates or the spread of drug resistance. The work will also provide reagents and bioinformatic resources that can be used by others studying P. vivax.