In vitro production of cat-restricted Toxoplasma pre-sexual stages

Ana Vera Antunes, Martina Shahinas, Christopher Swale, Dayana C. Farhat, Chandra Ramakrishnan, Christophe Bruley, Dominique Cannella, Marie G. Robert, Charlotte Corrao, Yohann Couté, Adrian B. Hehl, Alexandre Bougdour, Isabelle Coppens and Mohamed-Ali Hakimi ()
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Ana Vera Antunes: University Grenoble Alpes
Martina Shahinas: University Grenoble Alpes
Christopher Swale: University Grenoble Alpes
Dayana C. Farhat: University Grenoble Alpes
Chandra Ramakrishnan: University of Zurich
Christophe Bruley: University Grenoble Alpes, CEA, INSERM, UA13 BGE, CNRS, CEA
Dominique Cannella: University Grenoble Alpes
Marie G. Robert: University Grenoble Alpes
Charlotte Corrao: University Grenoble Alpes
Yohann Couté: University Grenoble Alpes, CEA, INSERM, UA13 BGE, CNRS, CEA
Adrian B. Hehl: University of Zurich
Alexandre Bougdour: University Grenoble Alpes
Isabelle Coppens: Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health and Malaria Research Institute
Mohamed-Ali Hakimi: University Grenoble Alpes

Nature, 2024, vol. 625, issue 7994, 366-376

Abstract: Abstract Sexual reproduction of Toxoplasma gondii, confined to the felid gut, remains largely uncharted owing to ethical concerns regarding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1,2. Here we found that the transcription factors AP2XII-1 and AP2XI-2 operate during the tachyzoite stage, a hallmark of acute toxoplasmosis, to silence genes necessary for merozoites, a developmental stage critical for subsequent sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a marked change in the transcriptional program, promoting a full transition from tachyzoites to merozoites. These in vitro-cultured pre-gametes have unique protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit MORC and HDAC3 (ref. 1), thereby limiting chromatin accessibility and transcription. Consequently, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. Successful production of merozoites in vitro paves the way for future studies on Toxoplasma sexual development without the need for cat infections and holds promise for the development of therapies to prevent parasite transmission.

Date: 2024
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DOI: 10.1038/s41586-023-06821-y

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