Cell cycle progression in malaria parasites (JANUS)

All eukaryotic cell multiplication requires well-orchestrated developmental programs and regulatory pathways to guarantee fidelity in transmission of genetic information. Multiplication inside red blood cells of Plasmodium falciparum, the deadliest malaria parasite, is responsible for malaria pathogenicity. Unlike model organisms, Plasmodium divides in unconventional ways producing not two but up to tens of thousands of daughter cells, in a single cell cycle round. This points to a yet-to-be-explored original and divergent cell cycle architecture where conventional rules likely do not apply. The hypothesis is that a transcriptional clock paces the cell cycle while a network of local players modulates and fine-tunes the activity of effectors through phosphorylation. To test this hypothesis, single cell transcriptomics and high resolution phospho-proteomics will first be used to understand how these are connected with cell cycle events and their contribution to normal progression and controlled cell cycle arrest. Secondly, a genome-scale conditional genetic screen will be conducted to identify cell cycle regulators – progression of pooled barcoded mutants will be mapped using cell cycle reporters, barseq and single cell transcriptomic readouts. Finally, the data collected throughout the JANUS project will be combined to provide an integrated model of cell cycle progression, checkpoints, their associated transcriptional and signalling events, and their interdependence. Furthermore, the study will functionally dissect on a gene-by-gene basis the entrance into the replicative phase based on our modelled data. Altogether the JANUS project will provide insights into an ancient, yet divergent process, essential for parasite survival and propagation with unprecedented detail. It may reveal innovative eukaryotic adaptations to cell cycle control in this basal lineage which could generate new insights into protist biology and provide new tools in the continuing fight against malaria.

Project details

Basic Science

Jul 2024 — Jun 2029

$1.62M

France