Cell cycle progression in malaria parasites

Introduction

All eukaryotic cell multiplication requires well-orchestrated developmental programs and regulatory pathways to guarantee fidelity in the transmission of genetic information. Multiplication inside red blood cells of Plasmodium falciparum, the deadliest malaria parasite, is responsible for malaria pathogenicity.

Unique Cell Division Mechanism

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.

Hypothesis

We hypothesize that a transcriptional clock paces the cell cycle while a network of local players modulates and fine-tunes the activity of effectors through phosphorylation.

Methodology

To test this hypothesis, we will:

1. Use single-cell transcriptomics and high-resolution phospho-proteomics to understand how these are connected with cell cycle events and their contribution to normal progression and controlled cell cycle arrest.
2. Conduct a genome-scale conditional genetic screen to identify cell cycle regulators. We will map the progression of pooled barcoded mutants using cell cycle reporters, barseq, and single-cell transcriptomic readouts.
3. Combine the data collected throughout the JANUS project and provide an integrated model of cell cycle progression, checkpoints, their associated transcriptional and signaling events, and their interdependence.

Functional Dissection

Furthermore, we will functionally dissect on a gene-by-gene basis the entrance into the replicative phase based on our modeled data.

Conclusion

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.