Tadalafil impacts the mechanical properties of Plasmodium falciparum gametocyte-infected erythrocytes

N’Dri, Marie-Esther; Royer, Ludivine; Lavazec, Catherine

doi:10.1016/j.molbiopara.2021.111392

Cited by 4 publications

(6 citation statements)

References 23 publications

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“…Seven hours after injection of 6x10 7 untreated mature GIE expressing luciferase, the luminescence signal in the spleen was very weak, however the signal was much higher when mice were injected with mature GIE pre-incubated with 100 µM tadalafil ( Figures 3D, E ). These results show that chemically-induced stiffening of mature GIE induces their retention in the spleen in vivo and therefore validate our previous results observed in an in vitro model for splenic retention ( Ramdani et al., 2015 ; N’dri et al., 2021 ).…”

Section: Resultssupporting

confidence: 91%

“…Targeting the mechanical properties of mature GIE to interfere with their circulation across the spleen has been proposed as a promising strategy to block malaria parasite transmission ( Tiburcio et al., 2012 ; Duez et al., 2015 ; Russell and Cooke, 2017 ; Henry et al., 2020 ). In this context, the PDE inhibitors sildenafil and tadalafil have previously shown their ability to block the filtration of mature GIE in an in vitro model of splenic retention ( Ramdani et al., 2015 ; N’dri et al., 2021 ). In this study, we used a humanized mouse model to address in vivo the effect of tadalafil on the circulation of mature GIE.…”

Section: Discussionmentioning

confidence: 99%

“…Pf PDEδ, the main PDE expressed by mature gametocyte stages, plays a key role in this process and appears to be the master regulator of mature GIE deformability ( Ramdani et al., 2015 ). Importantly, studies using an in vitro model for splenic retention reported that the marketed PDE inhibitors sildenafil and tadalafil increase the stiffness of mature GIE ( Ramdani et al., 2015 ; N’dri et al., 2021 ). These observations suggest that drugs targeting PDE are expected to promote the mechanical retention of mature GIE by the spleen and their clearance from the bloodstream in gametocyte carriers.…”

Section: Introductionmentioning

confidence: 99%

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The Phosphodiesterase Inhibitor Tadalafil Promotes Splenic Retention of Plasmodium falciparum Gametocytes in Humanized Mice

Barbieri

Gómez

Royer

et al. 2022

Front. Cell. Infect. Microbiol.

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The persistence of erythrocytes infected with Plasmodium falciparum gametocytes in the bloodstream is closely related to the modulation of their mechanical properties. New drugs that increase the stiffness of infected erythrocytes may thus represent a novel approach to block malaria parasite transmission. The phosphodiesterase inhibitor tadalafil has been shown to impair the ability of infected erythrocytes to circulate in an in vitro model for splenic retention. Here, we used a humanized mouse model to address in vivo the effect of tadalafil on the circulation kinetics of mature gametocyte-infected erythrocytes. We show that stiff immature gametocyte-infected erythrocytes are retained in the spleen of humanized mice at rates comparable to that of the in vitro model. Accordingly, tadalafil-induced stiffening of mature gametocyte-infected erythrocytes impairs their circulation in the bloodstream and triggers their retention by the spleen. These in vivo results validate that tadalafil is a novel drug lead potentially capable of blocking malaria parasite transmission by targeting GIE mechanical properties.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Phosphodiesterase Inhibitor Tadalafil Promotes Splenic Retention of Plasmodium falciparum Gametocytes in Humanized Mice

Barbieri

Gómez

Royer

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Finally, we tested sildenafil and tadalafil by DRA. Although these 2 drugs were not captured by the primary screen they have been previously reported to induce stiffening of stage V gametocytes 32 , 33 . IC 50 values were obtained for both killing effect and stiffening activity or, in some cases, one of them (Fig.…”

Section: Resultsmentioning

confidence: 99%

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

et al. 2023

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Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome (https://clinicaltrials.gov, ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.

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“…This decrease in phosphorylation is predicted to weaken their interactions with the ankyrin complex and thereby increase GIE deformability [61,62]. In line with the key role of PfPDEδ in this mechanism, incubation of mature GIE with PDE inhibitors, such as the marketed inhibitors sildenafil (Viagra®) or tadalafil (Cialis®), increases cAMP concentration in the infected cell and impairs their circulation in an in vitro model for splenic retention [62,63]. In accordance with these observations, treatment of P. berghei-infected mice with sildenafil increases gametocytes homing to the bone marrow and splenic cords, suggesting that PDE inhibitors may cause gametocytes to become mechanically trapped in sequestration sites [64].…”

mentioning

confidence: 97%

Host Cell Remodeling by Plasmodium falciparum Sexual Stages

Verdier

Neveu

Lavazec

2022

Curr. Tissue Microenviron. Rep.

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To thrive and survive, intracellular pathogens actively remodel their host cells. The sexual stages of the human malaria parasite Plasmodium falciparum, called gametocytes, develop in erythrocytes and have recently been shown to mature in nucleated erythroid precursors as well. Gametocytes deeply modify their erythrocyte host by exporting proteins to the host cell cytosol and membrane. These proteins induce dramatic changes in the morphology and physiology of the infected erythrocyte which acquires novel mechanical, adhesive and serologic properties. Some of these modifications play a key role for gametocyte sequestration in the bone marrow, subsequent release in the bloodstream and ability to persist in blood circulation. Erythroblast development is affected by gametocytes; however, it is still unclear whether erythroblasts undergo the same remodeling as their mature counterparts. Here we discuss the mechanisms developed by gametocytes to remodel their host erythrocyte and explore how the erythroblasts may be impacted by parasite development.

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Tadalafil impacts the mechanical properties of Plasmodium falciparum gametocyte-infected erythrocytes

Cited by 4 publications

References 23 publications

The Phosphodiesterase Inhibitor Tadalafil Promotes Splenic Retention of Plasmodium falciparum Gametocytes in Humanized Mice

The Phosphodiesterase Inhibitor Tadalafil Promotes Splenic Retention of Plasmodium falciparum Gametocytes in Humanized Mice

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Host Cell Remodeling by Plasmodium falciparum Sexual Stages

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