The Transcriptome of the Intraerythrocytic Developmental Cycle of Plasmodium falciparum

Abstract

Plasmodium falciparum is the causative agent of the most burdensome form of human malaria, affecting 200–300 million individuals per year worldwide. The recently sequenced genome of P. falciparum revealed over 5,400 genes, of which 60% encode proteins of unknown function. Insights into the biochemical function and regulation of these genes will provide the foundation for future drug and vaccine development efforts toward eradication of this disease. By analyzing the complete asexual intraerythrocytic developmental cycle (IDC) transcriptome of the HB3 strain of P. falciparum, we demonstrate that at least 60% of the genome is transcriptionally active during this stage. Our data demonstrate that this parasite has evolved an extremely specialized mode of transcriptional regulation that produces a continuous cascade of gene expression, beginning with genes corresponding to general cellular processes, such as protein synthesis, and ending with Plasmodium-specific functionalities, such as genes involved in erythrocyte invasion. The data reveal that genes contiguous along the chromosomes are rarely coregulated, while transcription from the plastid genome is highly coregulated and likely polycistronic. Comparative genomic hybridization between HB3 and the reference genome strain (3D7) was used to distinguish between genes not expressed during the IDC and genes not detected because of possible sequence variations. Genomic differences between these strains were found almost exclusively in the highly antigenic subtelomeric regions of chromosomes. The simple cascade of gene regulation that directs the asexual development of P. falciparum is unprecedented in eukaryotic biology. The transcriptome of the IDC resembles a “just-in-time” manufacturing process whereby induction of any given gene occurs once per cycle and only at a time when it is required. These data provide to our knowledge the first comprehensive view of the timing of transcription throughout the intraerythrocytic development of P. falciparum and provide a resource for the identification of new chemotherapeutic and vaccine candidates.

The malarial CDK Pfmrk and its effector PfMAT1 phosphorylate DNA replication proteins and co-localize in the nucleus

“…Although the in vivo phosphorylation status of these DNA replication components remains to be investigated, it is tempting to speculate that Pfmrk-mediated phosphorylation of PfRFC-5 and PfMCM6 may regulate the initiation of DNA replication. The microarray data of Pfmrk, PfMAT1 and Pfcyc-1 suggest high levels of expression from 4 to 28 h peaking at 8 and 24 h-several hours before the start of DNA replication [59]. PfMCM6 protein has been predominantly detected in late trophozoites and schizonts, and gene expression of both PfMCM-6 and PfRFC-5 peaks in late trophozoites through early schizonts-stages where most DNA replication is thought to occur [31,60].…”

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

“…Transcriptome analyses demonstrated that PfGluPho is expressed at a high level throughout the intraerythrocytic cycle of Plasmodium without showing stage-dependent differences (66,67).…”

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…1 A brief description of the Plasmodium falciparum (the most lethal malarial parasite) life cycle is required to better understand its molecular interactions in invasion. Following the bite of a malarial parasite-infected mosquito, the inoculated sporozoites (larva-like parasites present in the mosquito's salivary glands) migrate to the liver and invade hepatocytes through the interaction of a yet unknown large number of proteins [2][3][4] [step a in Figure 1A].…”