Colard-Itte, E. | bioRxiv Science

bioRxiv2025

An acyclic nucleoside phosphonate effectively blocks the egress of the malaria parasite by inhibiting the synthesis of cyclic GMP.

The urgent need for new antimalarial therapies arises from the alarming spread of malaria parasite resistance to existing drugs. A promising candidate, UA2239, an acyclic nucleoside phosphonate with a guanine as nucleobase, demonstrates rapid and irreversible cytotoxic effects on Plasmodium parasites, both in vitro and in an animal model. It blocks the active exit process, named egress, of merozoites and gametes from infected erythrocytes. UA2239 disrupts the essential cGMP-dependent egress pathway by decreasing cGMP levels in the parasite, making guanylate cyclase (PfGC) the most likely target. We also uncovered the remarkable molecular mechanism of resistance developed by parasites after prolonged exposure to the drug, which involves mutating not the target itself, but a downstream effector. The unique mechanism action of UA2239 makes it a valuable first-in-class candidate for further development and its ability to inhibit both parasite growth and transmission highlights its therapeutic potential as a dual-stage antimalarial agent.

microbiology↗

bioRxiv2025

Plasmodium falciparum PP1 phosphatase is a key regulator of malaria parasite transmission

For the successful transmission of malaria parasites from humans to mosquitoes, Plasmodium falciparum gametocytes must remain in the bloodstream long enough to be taken up by a mosquito. Once ingested, they are then activated into gametes to continue the parasite life cycle in the mosquito midgut. Both persistence of gametocytes in the blood and their activation into gametes are tightly regulated by phospho-signaling. While the serine-threonine phosphatase PfPP1 is an essential enzyme for parasite asexual proliferation, its role during transmission of sexual stages remains elusive. Here, we employed a conditional depletion strategy to conduct a functional analysis of PfPP1 during gametocyte development, gamete activation and transmission to mosquitoes. We show that PfPP1 regulates the deformability and the permeability of mature gametocyte-infected erythrocytes through the dephosphorylation of PKA substrates, thus highlighting a key role for PfPP1 in modulating the host cell mechanical properties, which are crucial for gametocyte persistence in the bloodstream. We also provide evidence that PfPP1 controls crucial steps of gamete activation via stimulation of the cGMP/ PKG pathway. Collectively, these results underscore the pivotal role of PfPP1 in the transmission of P. falciparum to the mosquito during both sexual development and gamete activation. AUTHOR SUMMARYThe protein phosphatase PP1 is a major contributor to total cellular phosphatase activity in eukaryotes and plays a critical role during various cellular processes. Here, we have unraveled novel mechanisms regulated by the phosphatase PfPP1 in the human malaria parasite Plasmodium falciparum. While PfPP1 is known to be essential for the parasite asexual proliferation, in the present study we demonstrate that PfPP1 is also required during the sexual parasite stages, called gametocytes, that ensure parasite transmission from humans to mosquitoes. PfPP1 is involved in regulating the mechanical properties of the gametocyte-infected host cell, a process necessary for the persistence of gametocytes in blood circulation. Moreover, PfPP1 also contributes to the activation of gametocytes into gametes, the stages able to pursue the parasite life cycle in mosquitoes. In addition to providing insights into novel mechanisms involved in parasite transmission, this study also highlights the possibility of interfering with PfPP1 signaling pathway for blocking malarial parasite transmission.

microbiology↗

bioRxiv2023

Genetic profiling of Plasmodium ovale wallikeri relapses with microsatellite markers and whole-genome sequencing

Like Plasmodium vivax, both Plasmodium ovale curtisi and Plasmodium ovale wallikeri have the ability to cause relapse in humans, defined as recurring asexual parasitaemia originating from liver dormant forms subsequent to a primary infection. Here, we investigated relapse patterns in P. ovale wallikeri infections from a cohort of travelers who were exposed to the parasite in Sub-Saharan Africa and then experienced relapses after their return to France. Using a novel set of eight highly polymorphic microsatellite markers, we genotyped 15 P. ovale wallikeri relapses. For most relapses, the paired primary and relapse infections were highly genetically related (with 12 being homologous), an observation that was confirmed by whole-genome sequencing for the four relapses we further studied. This is, to our knowledge, the first genetic evidence of relapses in P. ovale spp.

microbiology↗