Heterologous expression of interferon-stimulated genes reveals conserved anti-Toxoplasma properties between human and porcine cells

Toxoplasma is a zoonotic parasite that can cause life-threatening illness in humans and animals. The similarities in Toxoplasma pathogenesis between pigs and humans make pigs an attractive model for studying human toxoplasmosis. However, the mechanisms underpinning these similarities remain poorly understood. Since interferon-gamma (IFNγ) is crucial for immunity to Toxoplasma , we hypothesized that IFNγ signaling pathways conserved between humans and pigs contribute to comparable Toxoplasma pathogenesis. Using a genetic gain-of-function strategy, we observed that human or porcine interferon regulatory factor 1 (IRF1) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibited Toxoplasma replication in both homologous and heterologous human and porcine cells. IRF1-depleted porcine cells that failed to control Toxoplasma growth could be rescued by ectopic expression of human IRF1, which induces genes similar to those regulated by porcine IRF1. The expression of either human or pig IRF1 dampened Toxoplasma- induced transcriptional remodeling of porcine genes. Additionally, blocking IDO1 using 1-methyl tryptophan reversed parasite growth inhibition in cells expressing heterologous or homologous IDO1. These findings highlight conserved IFN-induced anti- Toxoplasma mechanisms between pigs and humans and enhance the potential of pigs as large animal models for human toxoplasmosis.