TargetingToxoplasma gondiiCPSF3 as a new approach to control toxoplasmosis.
Toxoplasma gondiiis 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 potentin vitroactivity againstT. gondiiParasites selected to be resistant to AN3661 had mutations inTgCPSF3, 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 inTgCPSF3introduced into wild-type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected withT. gondiiand treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore,TgCPSF3 is a promising novel target ofT. gondiithat provides an opportunity for the development of anti-parasitic drugs.
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France andres.palencia@univ-grenoble-alpes.fr alexandre.bougdour@univ-grenoble-alpes.fr mohamed-ali.hakimi@univ-grenoble-alpes.fr.|European 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, France.
Andrés
0000-0002-1805-319X
A
Palencia
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France andres.palencia@univ-grenoble-alpes.fr alexandre.bougdour@univ-grenoble-alpes.fr mohamed-ali.hakimi@univ-grenoble-alpes.fr.
Alexandre
0000-0002-5895-0020
A
Bougdour
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Marie-Pierre
MP
Brenier-Pinchart
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Bastien
B
Touquet
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Rose-Laurence
RL
Bertini
European 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, France.
Cristina
C
Sensi
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Gabrielle
G
Gay
Institute for Advanced Biosciences (IAB), OPTIMAL Small Animal Imaging Facility, Grenoble, France.
Julien
J
Vollaire
Institute for Advanced Biosciences (IAB), OPTIMAL Small Animal Imaging Facility, Grenoble, France.
Véronique
V
Josserand
Anacor Pharmaceuticals Inc., Palo Alto, CA, USA.
Eric
E
Easom
Anacor Pharmaceuticals Inc., Palo Alto, CA, USA.
Yvonne R
YR
Freund
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Hervé
H
Pelloux
Department of Medicine, University of California, San Francisco, CA, USA.
Philip J
PJ
Rosenthal
European 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, France.
Stephen
S
Cusack
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France andres.palencia@univ-grenoble-alpes.fr alexandre.bougdour@univ-grenoble-alpes.fr mohamed-ali.hakimi@univ-grenoble-alpes.fr.
Mohamed-Ali
0000-0002-2547-8233
MA
Hakimi
D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001896:Boron Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D039223:Cleavage And Polyadenylation Specificity Factor / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004351:Drug Resistance; D051379:Mice; D021261:Parasitic Sensitivity Tests; D017354:Point Mutation; D016019:Survival Analysis; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology*; D014123:Toxoplasmosis / Q000188:drug therapy*
D000981:Antiprotozoal Agents; D001896:Boron Compounds; D039223:Cleavage And Polyadenylation Specificity Factor

Toxoplasma gondii
; CPSF3; benzoxaborole; drug discovery; mRNA processing; toxoplasmosis