Eryptosis as a New Insight in Malaria Pathogenesis

Scovino, Aline Miranda; Totino, Paulo Renato Rivas; Morrot, Alexandre

doi:10.3389/fimmu.2022.855795

Cited by 15 publications

(8 citation statements)

References 77 publications

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“…RBC-targeting inhibitors may elicit toxicity through off-target activity or activity secondary to engagement of the primary, annotated target. Some drugs stimulate reactive oxygen species ( Deavall et al., 2012 ), and for erythrocytes oxidative damage can induce eryptosis and rapid clearance from the bloodstream ( Dreischer et al., 2022 ; Scovino et al., 2022 ). As a proxy for erythrotoxic action of small molecules, we measured phosphatidylserine (PS) exposure ( Dreischer et al., 2022 ; Scovino et al., 2022 ) and hemolysis following treatment of RBCs by flow-cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…Some drugs stimulate reactive oxygen species ( Deavall et al., 2012 ), and for erythrocytes oxidative damage can induce eryptosis and rapid clearance from the bloodstream ( Dreischer et al., 2022 ; Scovino et al., 2022 ). As a proxy for erythrotoxic action of small molecules, we measured phosphatidylserine (PS) exposure ( Dreischer et al., 2022 ; Scovino et al., 2022 ) and hemolysis following treatment of RBCs by flow-cytometry. Among the durably acting antimalarial inhibitors ( Figure 2 ), Yoda1 and IPA-3 elicited the most profound effect (~30-60% of RBCs with PS exposure at 24h), with Yoda1 also exhibiting a rapid onset of hemolysis comparable to control compound A23187 ( Figure 3 ; Supplementary Table 1 ) – both compounds have previously been reported to stimulate eryptosis ( Zelenak et al., 2011 ; Wadud et al., 2020 ).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Groomes,

Paul,

Duraisingh

2024

Front. Cell. Infect. Microbiol.

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BackgroundChemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases.MethodsOur overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in Plasmodium falciparum infection. Alongside P. falciparum, we implemented in vitro parasite susceptibility assays also in the zoonotic parasite Plasmodium knowlesi and the veterinary parasite Babesia divergens. We additionally carried out assays to test directly for action on RBCs apart from the parasites. To distinguish specific host-targeting antiparasitic activity from erythrotoxicity, we measured phosphatidylserine exposure and hemolysis stimulated by small molecules in uninfected RBCs.ResultsWe identified diverse RBC target-annotated inhibitors with Plasmodium-specific, Babesia-specific, and broad-spectrum antiparasitic activity. The anticancer MEK-targeting drug trametinib is shown here to act with submicromolar activity to block proliferation of Plasmodium spp. in RBCs. Some inhibitors exhibit antimalarial activity with transient exposure to RBCs prior to infection with parasites, providing evidence for host-targeting activity distinct from direct inhibition of the parasite.ConclusionsWe report here characterization of small molecules for antiproliferative and host cell-targeting activity for malaria and babesiosis parasites. This resource is relevant for assessment of physiological RBC-parasite interactions and may inform drug development and repurposing efforts.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Groomes,

Paul,

Duraisingh

2024

Front. Cell. Infect. Microbiol.

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“…Results show that transforming an image of qPCR-to qPCR+ necessitates generation of more anemia cells. Indeed the translation from a blood cell of a healthy patient to the blood cell of an infected patient seems to wipe a part of the hemoglobin content which, while not specific to the malaria infection, tends to denote an infectious context (White 2018; Scovino, Totino, and Morrot 2022). Furthermore, we also found that some cells were transformed into crenated cells which were previously reported to be related to certain liver diseases (Privitera and Meli 2016).…”

Section: Resultsmentioning

confidence: 99%

Revealing invisible cell phenotypes with conditional generative modeling

Lamiable

Champetier

Leonardi

et al. 2022

Preprint

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Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and observation. Aside from dramatic events such as cell division or cell death, most cell phenotypic changes that keep cells alive are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. While we show that deep learning models can leverage invisible features from microscopy images, to discriminate between close conditions, these features can yet hardly be observed and therefore interpreted. In this work, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases such as high concentration drug treatments, nuclear translocation and golgi apparatus assays. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs or low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to the accessible discovery of biological and disease biomarkers.

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“…On the other hand, not only infected RBCs undergo this cell death. This phenomenon is also common for non-infected cells, which may worsen anemia in patients with malaria [18]. Despite the numerous knowledge gaps in understanding the physiology and pathophysiology of eryptosis, its pharmacological modulation with therapeutic intentions has been widely investigated, in particular, in case of malaria [19].…”

Section: Introductionmentioning

confidence: 99%

Rare-earth orthovanadate nanoparticles trigger Ca²⁺-dependent eryptosis

Yefimova

Onishchenko²,

Klochkov³

et al. 2023

Nanotechnology

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Introduction. Rare-earth orthovanadate nanoparticles (ReVO4:Eu3+, Re = Gd, Y or La) are promising agents for photodynamic therapy of cancer due to their modifiable redox properties. However, their toxicity limits their application. Objective. The aim of this research was to elucidate pro-eryptotic effects of GdVO4:Eu3+ and LaVO4:Eu3+ nanoparticles with identification of underlying mechanisms of eryptosis induction and to determine their pharmacological potential in eryptosis-related diseases. Methods. Blood samples (n=9) were incubated for 24 h with 0-10-20-40-80 mg/L GdVO4:Eu3+ or LaVO4:Eu3+ nanoparticles, washed and used to prepare erythrocyte suspensions to analyze the cell membrane scrambling (annexin-V-FITC staining), cell shrinkage (forward scatter signaling), reactive oxygen species (ROS) generation through 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) staining and intracellular Ca2+ levels via FLUO4 AM staining by flow cytometry. Internalization of europium-enabled luminescent GdVO4:Eu3+ and LaVO4:Eu3+ nanoparticles was assessed by confocal laser scanning microscopy. Results. Both nanoparticles triggered eryptosis at concentrations of 80 mg/L. ROS-mediated mechanisms were not involved in rare-earth orthovanadate nanoparticles-induced eryptosis. Elevated cytosolic Ca2+ concentrations were revealed even at subtoxic concentrations of nanoparticles. LaVO4:Eu3+ nanoparticles increased intracellular calcium levels in a more pronounced way compared with GdVO4:Eu3+ nanoparticles. Our data disclose that the small-sized (15 nm) GdVO4:Eu3+ nanoparticles were internalized after a 24 h incubation, while the large-sized (~30 nm) LaVO4:Eu3+ nanoparticles were localized preferentially around erythrocytes. Conclusions. Both internalized GdVO4:Eu3+ and non-internalized LaVO4:Eu3+ nanoparticles (80 mg / L) promote eryptosis of erythrocytes after a 24 h exposure in vitro via Ca2+ signaling without involvement of oxidative stress. Eryptosis is a promising model for assessing nanotoxicity.

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Eryptosis as a New Insight in Malaria Pathogenesis

Cited by 15 publications

References 77 publications

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Revealing invisible cell phenotypes with conditional generative modeling

Rare-earth orthovanadate nanoparticles trigger Ca²⁺-dependent eryptosis

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Eryptosis as a New Insight in Malaria Pathogenesis

Cited by 15 publications

References 77 publications

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

Revealing invisible cell phenotypes with conditional generative modeling

Rare-earth orthovanadate nanoparticles trigger Ca2+-dependent eryptosis

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Resources

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Rare-earth orthovanadate nanoparticles trigger Ca²⁺-dependent eryptosis