Contribution of the phosphatase PfPP1 to the control of the malaria parasite life cycle: a focus on egress and gametocytes biology – PALP1

The phylum Apicomplexa comprises parasites of human and veterinary importance, among which Plasmodium falciparum, the deadliest Plasmodium species responsible for human malaria. This parasite displays a complex life cycle alternating between its mosquito vector and the human host. The symptomatic phase of the disease corresponds to the intra-erythrocytic cycle, whereby the parasite repeatedly invades a red blood cell (RBC), multiply in the host within a parasitophorous vacuole (PV) to form new invasive parasites that will be released in the blood circulation upon sequential rupture of the surrounding PV and RBC membranes. During the erythrocytic cycle, some parasites will differentiate into sexual stages named gametocytes that will allow the transmission of the parasite to its mosquito vector. Once ingested during a blood meal, gametocytes are activated, exit from the RBC and convert into fertile gametes in a process called gametogenesis.Exit of asexual parasites from the RBC, also known as the egress step, is timely controlled and coordinated with the completion of the replication process, but the cues that trigger its initiation remain to be identified. Recently, morphological modifications of the PV have been reported to take place between the end of parasite multiplication and the rupture of the PV membrane, but the molecular effectors involved in these early steps of egress are currently unknown. What is clear though is that the egress cascade relies on a complex phospho-signalling pathway involving two parasite kinases: the cGMP-dependent protein kinase G (PKG) and the calcium-dependent kinase CDPK5. Their activation leads to the discharge of secretory organelles, whose content participates in the subsequent disruption of the surrounding PV and RBC membranes. The researchers have identified the parasite phosphatase PP1 (PP1) as a regulator of egress, notably by regulating the phosphorylation status of guanylate cyclase alpha, the enzyme that generates the signaling molecule cGMP responsible for PKG activation. The positioning of PP1 upstream of PKG in the signaling cascade makes it an attractive candidate to regulate the early steps of egress that are poorly understood. Interestingly, asexual blood-stage egress and gametes egress share many common effectors and signalling molecules including a cGMP-dependent signalling cascade, suggesting the conservation of the egress mechanism at the molecular level. The better understanding of PP1 functions in Plasmodium biology and egress may open the avenue for future intervention strategies and lead to novel multi-stage antimalarial drugs with therapeutic and transmission-blocking activities.
 

Project details

Genetics and Genomics

Dec 2021 — Dec 2025

$485,584

France