title: Plasmodium falciparum exhibits markers of regulated cell death at high population density in vitro.
abstract: The asexual erythrocytic cycle of the protozoan parasite Plasmodium falciparum is responsible for the pathogenesis of malaria and causes the overwhelming majority of malaria deaths. Rapidly increasing parasitaemia during this 48hour cycle threatens the survival of the human host and the parasite prior to transmission of the slow-maturing sexual stages to the mosquito host. The parasite may utilise regulated cell death (RCD) to control the burden of infection on the host and thus aid its own survival and transmission. The occurrence of RCD in P. falciparum remains a controversial topic. We provide strong evidence for the occurrence of an apoptosis-like phenotype of RCD in P. falciparum under conditions of high parasite density. P. falciparum was maintained in vitro and stressed by allowing growth to an unrestricted peak parasitaemia. Cell death markers, including morphological changes, DNA fragmentation, mitochondrial polarisation and phosphatidylserine externalisation were used to characterise parasite death at the time of peak parasitaemia and 24h later. At peak parasitaemia, mitochondrial depolarisation was observed, together with phosphatidylserine externalisation in both parasitised- and neighbouring non-infected erythrocytes. DNA fragmentation coincided with a decline in parasitaemia. Fewer merozoites were observed in mature schizonts at peak parasitaemia. Growth recovery to near-peak parasitaemia was noted within two intraerythrocytic cycles. The combination and chronological order of the biochemical markers of cell death suggest the occurrence of an apoptosis-like phenotype. The identification of a RCD pathway in P. falciparum may provide novel drug targets, particularly if the pathway differs from the host machinery.
authors.affiliation: Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: DewaldtEngelbrecht@gmail.com.
authors.forename: Dewaldt
authors.initials: D
authors.lastname: Engelbrecht
authors.affiliation: Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa; National Health Laboratory Service, Johannesburg, South Africa. Electronic address: theresa.coetzer@nhls.ac.za.
authors.forename: Thérèsa Louise
authors.initials: TL
authors.lastname: Coetzer
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D009033:Culicidae / Q000469:parasitology; D053938:DNA Fragmentation; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D052940:Merozoites / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D018512:Parasitemia / Q000473:pathology*; D010718:Phosphatidylserines / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity; D011156:Population Density; D052939:Schizonts / Q000254:growth & development
chemical_list: D010718:Phosphatidylserines
keywords: DNA fragmentation; High parasitaemia; Mitochondrial depolarisation; Phosphatidylserine externalisation; Plasmodium falciparum; Regulated cell death