Postgenomic Strategies and the Search for Cure

Via sequencing of various parasite genomes and subsequent gene annotation, it is possible to predict the complete set of theoretical parasite gene products. Post-genome-sequence analyses attempt to confirm, support, and extend the genome annotation via hypothesis-based experimentation into the biological aspects of the parasite's life cycle. In the parasitic protists for which sufficient sequence information is available, techniques are being applied for studying large-scale gene expression. Recent methodologies to identify proteins as research targets include "post-genomic" techniques such as the serial analysis of gene expression (SAGE), microarray screening, and proteomics. Delineation of life cycle stages of expression, followed by cellular localization studies, might provide clues as to how complex parasitic protists interact with their hosts, respond to drugs, and develop mechanisms of immune evasion or drug resistance. For the malaria parasite, insights provided by analysis of the annotated genome will probably lead to the discovery of new drug targets based upon novel parasite-specific pathways, as well as the identification of novel extracellular proteins that may serve as candidates for vaccine targets. New information on the basis of resistance to existing drugs will facilitate the development of co-treatments to reduce or reverse drug resistance, rescuing previously highly successful treatment regimens for future use (e.g., chloroquine and the P.falciparum chloroquine-resistance transporter gene). Finally, genetic manipulation of both the parasite and the insect vector to create either attenuated strains or insects refractory to parasite invasion could produce therapeutic benefits.

Principal post-genomic strategies are discussed in the following paragraphs in more detail, using P. falciparum as an example.

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