Mitosis in the human malaria parasite Plasmodium falciparum.

EUKARYOTIC CELL, Apr. 2011, p. 474–482 1535-9778/11/$12.00 doi:10.1128/EC.00314-10 Copyright © 2011, American Society for Microbiology. All Rights Reserved. Vol. 10, No. 4 Mitosis in the Human Malaria Parasite Plasmodium falciparum䌤 Noel Gerald, Babita Mahajan, and Sanjai Kumar* Division of Emerging Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852 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. zoites assemble from the surface of the mother cell (61, 67), and these infective sporozoites then migrate to the mosquito salivary glands for transmission to the host. Of the thousands of sporozoites that are produced from a sporoblast, only a few will be transmitted to the vertebrate host when the mosquito takes another blood meal, and an even smaller number may reach the host liver for further development (60). In liver-stage schizogony (45), a single invading sporozoite grows as a trophozoite (1n to 2n) within a liver cell. The parasite then undergoes 13 to 14 rounds of DNA synthesis, mitosis, and nuclear division to produce a syncytial cell (schizont) with tens of thousands of nuclei. From the surface of this syncytial parasite, tens of thousands (16, 68) of haploid (1n) daughter liver-stage merozoites assemble and are eventually released into the bloodstream in parasite-filled vesicles called merosomes (77). Once released into the bloodstream, merozoites invade red blood cells and continue to expand their numbers with bloodstage schizogony (10). All of the clinical symptoms of malaria (fever, anemia, and neurological pathologies) are associated with the blood stage of the parasite life cycle (65). In bloodstage schizogony, following invasion, a single invading merozoite begins within the red blood cell as a ring stage and progresses into a trophozoite (1n to 2n) and then undergoes three to four rounds of DNA synthesis, mitosis, and nuclear division to produce a syncytial schizont with 16 to 22 nuclei (6, 10, 44, 53). In a synchronous mass division step, approximately 22 haploid (1n) daughter merozoites (depending on the species) assemble from the surface of the mother schizont, and with the rupture of the red blood cell, the new merozoites are released for more rounds of invasion and expansion (10, 44, 75). In nonimmune hosts, blood-stage parasites may undergo uncontrolled growth unless they are restricted by innate and adaptive immune responses. Splenic clearance is considered a major mechanism of this parasite growth regulation. However, the parasite has developed highly sophisticated mechanisms to evade immune-mediated clearance, such as expressing variant antigens on the surface of infected red cells to sequester them on endothelial cells in different organs. Nonetheless, in both immune and nonimmune hosts, the parasite burden can be SERIAL MITOSIS IS A COMMON THEME IN MALARIA PARASITE REPRODUCTION There 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 sporo* Corresponding author. Mailing address: DETTD/OBRR/CBER/ FDA, 1401 Rockville Pike (HFM-313), Rockville, MD 20852. Phone: (301) 827-7533. Fax: (301) 827-4622. E-mail: .gov. 䌤 Published ahead of print on 11 February 2011. 474 VOL. 10, 2011 maintained by repeated cycles of asexual schizogony from only a few intraerythrocytic parasites. Thus, the malaria parasite builds large populations from a relatively small number of founding members in every major stage of its development, and each time, the parasite relies on serial mitosis to accomplish this growth. These growth periods enable parasite transmission, and as a by-product, the toxins released by rupturing schizonts help to fuel the pathogenic symptoms of the disease. Similar reproductive strategies have been described for other apicomplexans, such as Sarcocystis (75, 80). This paper highlights some of the distinctive features of mitosis in Plasmodium parasites with a special emphasis on the mitotic spindle and microtubule organizing centers (MTOCs), and we will compare them to some of the visual hallmarks of traditional mitosis that are often associated with higher eukaryotes. TRADITIONAL VIEWS OF MITOSIS Histori (...truncated)