Mitosis in the Human Malaria Parasite Plasmodium falciparum

Abstract

Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes. SERIAL MITOSIS IS A COMMON THEME IN MALARIA PARASITE REPRODUCTIONThere are four critical points in the life cycle of Plasmodium parasites in which a small number of parasites rapidly multiply to generate much larger populations (60). These life cycle stages are male gamete development (72), sporozoite formation (5, 13), liver-stage development (68), and blood-stage asexual reproduction (9, 60). The first two of these processes occur within the mosquito vector, and the second two processes take place in the vertebrate host. During each of these Plasmodium life cycle stages, the parasites increase their numbers by using serial rounds of mitosis to create multinuclear cells and then orchestrating mass cytokinesis events to release their progeny (71). Mitosis is the process by which eukaryotic cells segregate their chromosomes in preparation for cell division (33,47,51).To create male gametes in preparation for sexual reproduction, the parasite begins with a haploid (1n) cell called a microgametocyte which is ingested by the mosquito during a blood meal (34,72). Within 12 min, this microgametocyte undergoes three rapid rounds of DNA synthesis and mitosis to generate a cell with an 8n genomic complement (35,36,73). Over the next 3 min, these genomes separate from one another and eight new haploid (1n) male gametes begin to assemble from the surface of the original cell (4, 69, 71).Within the mosquito midgut, a small number of the male gametes will fuse with female gametes that have also developed in this compartment, and this fusion will create diploid (2n) zygotes (15). These zygotes develop into motile ookinetes (4n) (36) that ultimately become embedded in the basal lamina beneath the midgut epithelial wall as oocysts (14). Over the course of several days, a single oocyst undergoes 10 to 11 rounds of DNA synthesis and mitosis to create a syncytial cell (sporoblast) with thousands of nuclei (61,70,82). In a massive cytokinesis event, thousands of haploid (1n) daughter sporozoites assemble from the surface of the mother cell (61, 67), and these infective sporozo...

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

“…During meiotic recombination, each chromosome averages one crossover (73,74,77) and has a genetic map unit distance of ϳ10 kb (77) to ϳ15 kb (73) per centimorgan. Meiosis is followed by many rounds of DNA replication inside oocysts to form thousands of genomes that segregate into individual haploid sporozoites (66,78).…”

A View on the Role of Epigenetics in the Biology of Malaria Parasites

“…Whether changes in subnuclear localization are also involved in activation of other clonally variant genes remains to be demonstrated. Considering that Plasmodium parasites undergo closed mitosis and that their chromosomes do not condensate during nuclear division [65], it is conceivable that the localization of a clonally variant gene within the nucleus may be maintained through nuclear division and consequently transmitted from one generation to the next, thus contributing to epigenetic inheritance of the expression status. Interplay between histone PTMs and subnuclear localization, such that one determines or reinforces the other, has been observed in other organisms [66].…”

Plasmodium berghei MAPK1 Displays Differential and Dynamic Subcellular Localizations during Liver Stage Development

“…In live cell imaging experiments, the GFP-tagged PbMAPK2 protein was found in, around and between the dividing parasite nuclei during schizogony, with a localization pattern resembling the distribution of α-tubulin observed in P. falciparum blood stage schizonts [3], [21], suggesting a function of this kinase in liver stage parasite karyokinesis. Correspondingly, detailed analysis of the defective male gametocyte development of MAPK2 knockout parasites revealed normal DNA synthesis but a failure in subsequent karyokinesis/cytokinesis [12], [14], [15], [22].…”

“…In the latter, metabolically active cells, Plasmodium parasites multiply at a tremendous rate, generating several thousands of merozoites in just a few days. Although nuclear division and subsequent organelle distribution during blood and liver stage schizogony/merogony have recently been described morphologically [3], [4], the intracellular signaling events underlying these processes and their rapid and reliable performance are still largely unknown. However, it was reasoned that protein kinases may play a role [3], [5].…”