GRA12 is a common virulence factor across Toxoplasma gondii strains and mouse subspecies

Francesca Torelli, Simon Butterworth, Eloise Lockyer, Ana N. Matias, Franziska Hildebrandt, Ok-Ryul Song, Jennifer Pearson-Farr and Moritz Treeck ()
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Francesca Torelli: The Francis Crick Institute
Simon Butterworth: The Francis Crick Institute
Eloise Lockyer: The Francis Crick Institute
Ana N. Matias: Gulbenkian Institute for Molecular Medicine
Franziska Hildebrandt: Gulbenkian Institute for Molecular Medicine
Ok-Ryul Song: The Francis Crick Institute
Jennifer Pearson-Farr: The Francis Crick Institute
Moritz Treeck: The Francis Crick Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Toxoplasma gondii parasites exhibit extraordinary host promiscuity owing to over 250 putative secreted proteins that disrupt host cell functions, enabling parasite persistence. However, most of the known effector proteins are specific to Toxoplasma genotypes or hosts. To identify virulence factors that function across different parasite isolates and mouse strains that differ in susceptibility to infection, we performed systematic pooled in vivo CRISPR-Cas9 screens targeting the Toxoplasma secretome. We identified several proteins required for infection across parasite strains and mouse species, of which the dense granule protein 12 (GRA12) emerged as the most important effector protein during acute infection. GRA12 deletion in IFNγ-activated macrophages results in collapsed parasitophorous vacuoles and increased host cell necrosis, which is partially rescued by inhibiting early parasite egress. GRA12 orthologues from related coccidian parasites, including Neospora caninum and Hammondia hammondi, complement TgΔGRA12 in vitro, suggesting a common mechanism of protection from immune clearance by their hosts.

Date: 2025
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DOI: 10.1038/s41467-025-58876-2

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