Evidence-Based Annotation of the Malaria Parasite's Genome Using Comparative Expression Profiling

Abstract

A fundamental problem in systems biology and whole genome sequence analysis is how to infer functions for the many uncharacterized proteins that are identified, whether they are conserved across organisms of different phyla or are phylum-specific. This problem is especially acute in pathogens, such as malaria parasites, where genetic and biochemical investigations are likely to be more difficult. Here we perform comparative expression analysis on Plasmodium parasite life cycle data derived from P. falciparum blood, sporozoite, zygote and ookinete stages, and P. yoelii mosquito oocyst and salivary gland sporozoites, blood and liver stages and show that type II fatty acid biosynthesis genes are upregulated in liver and insect stages relative to asexual blood stages. We also show that some universally uncharacterized genes with orthologs in Plasmodium species, Saccharomyces cerevisiae and humans show coordinated transcription patterns in large collections of human and yeast expression data and that the function of the uncharacterized genes can sometimes be predicted based on the expression patterns across these diverse organisms. We also use a comprehensive and unbiased literature mining method to predict which uncharacterized parasite-specific genes are likely to have roles in processes such as gliding motility, host-cell interactions, sporozoite stage, or rhoptry function. These analyses, together with protein-protein interaction data, provide probabilistic models that predict the function of 926 uncharacterized malaria genes and also suggest that malaria parasites may provide a simple model system for the study of some human processes. These data also provide a foundation for further studies of transcriptional regulation in malaria parasites.

Triclosan inhibit the growth of the late liver‐stage of Plasmodium

“…In vitro inhibition data demonstrated that triclosan was active against the liver-stage parasites. Our finding is in agreement with the prediction that fatty acid biosynthesis pathways could be potential drug targets of liver-stage parasite (21).…”

“…Triclosan inhibits fatty acid synthesis in bacteria by specifically targeting FabI (31)(32)(33). Recent proteomic (34), genomic (21), and real-time PCR analysis (22) of liver-stage parasites have shown the upregulation of enzymes of Type-II fatty acid synthesis. Blocking the activity of these upregulated enzymes may provide a solution for treating liver-stage infection.…”

“…In the case of humans, asymptomatic liver stage of infection lasts for about 7-13 days. Zhou et al (21) predicted that the liver-stage parasites might also be prone to inhibitors that interfere with Type-II fatty acid biosynthesis. Recent knockout (of FAS-II enzymes) studies further support the importance of this pathway in the development of liver-stage parasites (22,23).…”

A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

“…Our findings suggest that L3 is not potently cross-presented by dead or dying sporozoites and instead is probably targeted after synthesis by infected hepatocytes. This finding agrees with most expression studies in Plasmodium spp., which consistently find abundant L3 transcripts and protein in liver (39,40) and iRBC stages (41). Although low abundance L3 transcripts were detected in sporozoites (42,43), L3 protein was undetectable (44) or nearly undetectable (42,43) by mass spectrometry compared with later timepoints.…”

Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium

“…4 wpc gene family in P. falciparum and P. berghei [8,9] and four P. yoelii cpw-wpc genes were detected in gametocytes and young ookinetes [10]. Twenty-two cpw-wpc genes from three species are thus upregulated in gametocytes, suggesting a conserved role for this gene family during sexual development and transmission of the human and two rodent malaria species.…”