Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis
Abstract Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment disco...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201607370 |
| _version_ | 1797285135856435200 |
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| author | Andrés Palencia Alexandre Bougdour Marie‐Pierre Brenier‐Pinchart Bastien Touquet Rose‐Laurence Bertini Cristina Sensi Gabrielle Gay Julien Vollaire Véronique Josserand Eric Easom Yvonne R Freund Hervé Pelloux Philip J Rosenthal Stephen Cusack Mohamed‐Ali Hakimi |
| author_facet | Andrés Palencia Alexandre Bougdour Marie‐Pierre Brenier‐Pinchart Bastien Touquet Rose‐Laurence Bertini Cristina Sensi Gabrielle Gay Julien Vollaire Véronique Josserand Eric Easom Yvonne R Freund Hervé Pelloux Philip J Rosenthal Stephen Cusack Mohamed‐Ali Hakimi |
| author_sort | Andrés Palencia |
| collection | DOAJ |
| description | Abstract Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii. Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF‐73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes. Point mutations in TgCPSF3 introduced into wild‐type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected with T. gondii and treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore, TgCPSF3 is a promising novel target of T. gondii that provides an opportunity for the development of anti‐parasitic drugs. |
| first_indexed | 2024-03-07T17:58:48Z |
| format | Article |
| id | doaj.art-96892dd7fa464077a75b0e590d1fd393 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:58:48Z |
| publishDate | 2017-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-96892dd7fa464077a75b0e590d1fd3932024-03-02T11:23:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-03-019338539410.15252/emmm.201607370Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosisAndrés Palencia0Alexandre Bougdour1Marie‐Pierre Brenier‐Pinchart2Bastien Touquet3Rose‐Laurence Bertini4Cristina Sensi5Gabrielle Gay6Julien Vollaire7Véronique Josserand8Eric Easom9Yvonne R Freund10Hervé Pelloux11Philip J Rosenthal12Stephen Cusack13Mohamed‐Ali Hakimi14Institute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceEuropean Molecular Biology Laboratory (EMBL) Grenoble Outstation and Unit of Virus Host‐Cell Interactions University of Grenoble‐EMBL‐Centre National de la Recherche Scientifique Grenoble Cedex 9 FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceInstitute for Advanced Biosciences (IAB) OPTIMAL Small Animal Imaging Facility Grenoble FranceInstitute for Advanced Biosciences (IAB) OPTIMAL Small Animal Imaging Facility Grenoble FranceAnacor Pharmaceuticals Inc. Palo Alto CA USAAnacor Pharmaceuticals Inc. Palo Alto CA USAInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceDepartment of Medicine University of California San Francisco CA USAEuropean Molecular Biology Laboratory (EMBL) Grenoble Outstation and Unit of Virus Host‐Cell Interactions University of Grenoble‐EMBL‐Centre National de la Recherche Scientifique Grenoble Cedex 9 FranceInstitute for Advanced Biosciences (IAB) Team Host‐Pathogen Interactions & Immunity to Infection INSERM U1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceAbstract Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii. Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF‐73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes. Point mutations in TgCPSF3 introduced into wild‐type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected with T. gondii and treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore, TgCPSF3 is a promising novel target of T. gondii that provides an opportunity for the development of anti‐parasitic drugs.https://doi.org/10.15252/emmm.201607370benzoxaboroleCPSF3drug discoverymRNA processingToxoplasma gondiitoxoplasmosis |
| spellingShingle | Andrés Palencia Alexandre Bougdour Marie‐Pierre Brenier‐Pinchart Bastien Touquet Rose‐Laurence Bertini Cristina Sensi Gabrielle Gay Julien Vollaire Véronique Josserand Eric Easom Yvonne R Freund Hervé Pelloux Philip J Rosenthal Stephen Cusack Mohamed‐Ali Hakimi Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis EMBO Molecular Medicine benzoxaborole CPSF3 drug discovery mRNA processing Toxoplasma gondii toxoplasmosis |
| title | Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis |
| title_full | Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis |
| title_fullStr | Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis |
| title_full_unstemmed | Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis |
| title_short | Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis |
| title_sort | targeting toxoplasma gondii cpsf3 as a new approach to control toxoplasmosis |
| topic | benzoxaborole CPSF3 drug discovery mRNA processing Toxoplasma gondii toxoplasmosis |
| url | https://doi.org/10.15252/emmm.201607370 |
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