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An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum

Apicomplexa phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, Plasmodium falciparum and Toxoplasma gondii are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which ef...

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Autores principales: Honfozo, Ariane, Houngue, Rodrigue, Vandeputte, Alexandre, Dechavanne, Sébastien, Nouatin, Odilon, Atindehou, Ménonvè Cynthia, Fanou, Lucie Ayi, Massougbodji, Achille, Dechavanne, Célia, Brodin, Priscille, Tomavo, Stanislas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020723/
https://www.ncbi.nlm.nih.gov/pubmed/36936758
http://dx.doi.org/10.3389/fcimb.2023.1102551
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author Honfozo, Ariane
Houngue, Rodrigue
Vandeputte, Alexandre
Dechavanne, Sébastien
Nouatin, Odilon
Atindehou, Ménonvè Cynthia
Fanou, Lucie Ayi
Massougbodji, Achille
Dechavanne, Célia
Brodin, Priscille
Tomavo, Stanislas
author_facet Honfozo, Ariane
Houngue, Rodrigue
Vandeputte, Alexandre
Dechavanne, Sébastien
Nouatin, Odilon
Atindehou, Ménonvè Cynthia
Fanou, Lucie Ayi
Massougbodji, Achille
Dechavanne, Célia
Brodin, Priscille
Tomavo, Stanislas
author_sort Honfozo, Ariane
collection PubMed
description Apicomplexa phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, Plasmodium falciparum and Toxoplasma gondii are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which efficient vaccines are presently lacking and therapies need to be improved. Apicomplexan parasites have a highly polarized morphology, with their apical end containing specific secretory organelles named rhoptries and micronemes, which depend on the unique receptor and transporter sortilin TgSORT for their biogenesis. In the present study, we took advantage of the subcellular polarity of the parasite to engineer a clonal transgenic Toxoplasma line that expresses simultaneously the green fluorescent protein TgSORT-GFP in the post-Golgi-endosome-like compartment and the red fluorescent protein rhoptry ROP1-mCherry near the apical end. We utilized this fluorescent transgenic T. gondii to develop a miniaturized image-based phenotype assay coupled to an automated image analysis. By applying this methodology to 1,120 compounds, we identified 12 that are capable of disrupting the T. gondii morphology and inhibiting intracellular replication. Analysis of the selected compounds confirmed that all 12 are kinase inhibitors and intramembrane pumps, with some exhibiting potent activity against Plasmodium falciparum. Our findings highlight the advantage of comparative and targeted phenotypic analysis involving two related parasite species as a means of identifying molecules with a conserved mode of action.
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spelling pubmed-100207232023-03-18 An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum Honfozo, Ariane Houngue, Rodrigue Vandeputte, Alexandre Dechavanne, Sébastien Nouatin, Odilon Atindehou, Ménonvè Cynthia Fanou, Lucie Ayi Massougbodji, Achille Dechavanne, Célia Brodin, Priscille Tomavo, Stanislas Front Cell Infect Microbiol Cellular and Infection Microbiology Apicomplexa phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, Plasmodium falciparum and Toxoplasma gondii are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which efficient vaccines are presently lacking and therapies need to be improved. Apicomplexan parasites have a highly polarized morphology, with their apical end containing specific secretory organelles named rhoptries and micronemes, which depend on the unique receptor and transporter sortilin TgSORT for their biogenesis. In the present study, we took advantage of the subcellular polarity of the parasite to engineer a clonal transgenic Toxoplasma line that expresses simultaneously the green fluorescent protein TgSORT-GFP in the post-Golgi-endosome-like compartment and the red fluorescent protein rhoptry ROP1-mCherry near the apical end. We utilized this fluorescent transgenic T. gondii to develop a miniaturized image-based phenotype assay coupled to an automated image analysis. By applying this methodology to 1,120 compounds, we identified 12 that are capable of disrupting the T. gondii morphology and inhibiting intracellular replication. Analysis of the selected compounds confirmed that all 12 are kinase inhibitors and intramembrane pumps, with some exhibiting potent activity against Plasmodium falciparum. Our findings highlight the advantage of comparative and targeted phenotypic analysis involving two related parasite species as a means of identifying molecules with a conserved mode of action. Frontiers Media S.A. 2023-03-03 /pmc/articles/PMC10020723/ /pubmed/36936758 http://dx.doi.org/10.3389/fcimb.2023.1102551 Text en Copyright © 2023 Honfozo, Houngue, Vandeputte, Dechavanne, Nouatin, Atindehou, Fanou, Massougbodji, Dechavanne, Brodin and Tomavo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Honfozo, Ariane
Houngue, Rodrigue
Vandeputte, Alexandre
Dechavanne, Sébastien
Nouatin, Odilon
Atindehou, Ménonvè Cynthia
Fanou, Lucie Ayi
Massougbodji, Achille
Dechavanne, Célia
Brodin, Priscille
Tomavo, Stanislas
An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title_full An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title_fullStr An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title_full_unstemmed An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title_short An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum
title_sort image-based high-content screening for compounds targeting toxoplasma gondii repurposed inhibitors effective against the malaria parasite plasmodium falciparum
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020723/
https://www.ncbi.nlm.nih.gov/pubmed/36936758
http://dx.doi.org/10.3389/fcimb.2023.1102551
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