The progression of the intra-erythrocytic cell cycle of Plasmodium falciparum and the role of the centriolar plaques in asynchronous mitotic division during schizogony

The cell division cycle and mitosis of intra-erythrocytic (IE) Plasmodium falciparum are poorly understood aspects of parasite development which affect malaria molecular pathogenesis. Specifically, the timing of the multiple gap (G), DNA synthesis (S) and chromosome separation (M) phases of parasite mitosis are not well defined, nor whether genome divisions are immediately followed by cleavage of the nuclear envelope. Curiously, daughter merozoite numbers do not follow the geometric expansion expected from equal numbers of binary divisions, an outcome difficult to explain using the standard model of cell cycle regulation. Using controlled synchronisation techniques, confocal microscopy to visualise key organelles and fluorescence in situ hybridization (FISH) to follow the movements and replication of genes and telomeres, we have re-analysed the timing and progression of mitotic events. The asynchronous duplications of the P. falciparum centrosome equivalents, the centriolar plaques, are established and these are correlated with chromosome and nuclear divisions in a new model of P. falciparum schizogony. Our results improve the resolution of the cell cycle and its phases during P. falciparum IE development, showing that asynchronous, independent nuclear division occurs during schizogony, with the centriolar plaques playing a major role in regulating mitotic progression.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (31 K)Download as PowerPoint slideResearch highlights► The mitosis of intra-erythrocytic (IE) Plasmodium falciparum is intimately related to malaria molecular pathogenesis. However the initiation and progression of mitotic phases are not well defined, nor whether successive genome divisions are immediately followed by cleavage of the nuclear envelope. ► Daughter merozoite numbers do not conform to the numbers predicted by successive binary division of the haploid genome, which conflicts with standard models of cell cycle regulation. ► Using confocal microscopy to visualize key organelles and follow the replication of genes and telomeres, we have conducted a novel analysis of the initiation and progression of mitotic events. ► The asynchronous duplications of the P. falciparum centrosome equivalents, the centriolar plaques, are established and these are correlated with asynchronous nuclear division in a new model of the progression of P. falciparum intra-erythrocytic schizogony.