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FEBS J. 2018 Mar;285(5):848-870. doi: 10.1111/febs.14370. Epub 2018 Jan 11.

A high parasite density environment induces transcriptional changes and cell death in Plasmodium falciparum blood stages.

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Bio21 Institute for Molecular Science and Biotechnology and School of BioSciences, University of Melbourne, Parkville, VIC., Australia.
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, NY, USA.
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC., Australia.
Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK.
Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC., Australia.
Department of Medicine, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.


Transient regulation of Plasmodium numbers below the density that induces fever has been observed in chronic malaria infections in humans. This species transcending control cannot be explained by immunity alone. Using an in vitro system we have observed density dependent regulation of malaria population size as a mechanism to possibly explain these in vivo observations. Specifically, Plasmodium falciparum blood stages from a high but not low-density environment exhibited unique phenotypic changes during the late trophozoite (LT) and schizont stages of the intraerythrocytic cycle. These included in order of appearance: failure of schizonts to mature and merozoites to replicate, apoptotic-like morphological changes including shrinking, loss of mitochondrial membrane potential, and blebbing with eventual release of aberrant parasites from infected erythrocytes. This unique death phenotype was triggered in a stage-specific manner by sensing of a high-density culture environment. Conditions of glucose starvation, nutrient depletion, and high lactate could not induce the phenotype. A high-density culture environment induced rapid global changes in the parasite transcriptome including differential expression of genes involved in cell remodeling, clonal antigenic variation, metabolism, and cell death pathways including an apoptosis-associated metacaspase gene. This transcriptional profile was also characterized by concomitant expression of asexual and sexual stage-specific genes. The data show strong evidence to support our hypothesis that density sensing exists in P. falciparum. They indicate that an apoptotic-like mechanism may play a role in P. falciparum density regulation, which, as in yeast, has features quite distinguishable from mammalian apoptosis.


Gene expression data are available in the GEO databases under the accession number GSE91188.


Plasmodium falciparum ; density; microarray; stress response; transcription

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