Tissue-specific transcriptomic responses to early Toxoplasma gondii infection in sheep during congenital toxoplasmosis

Toxoplasma gondii is a widespread zoonotic pathogen of major One Health concern, capable of causing congenital toxoplasmosis in both humans and sheep. Despite its impact, early host–parasite molecular interactions during acute infection in pregnant hosts remain largely unexplored. In this study, we characterized the transcriptomic responses of key tissues involved in early infection (the small intestine, mesenteric lymph nodes, and placenta) in pregnant ewes experimentally infected with T. gondii strain TgShSp1. RNA-seq analysis revealed pronounced, tissue-specific transcriptional changes at 6 days post-infection (dpi), particularly in the mesenteric lymph nodes, characterized by activation of interferon- and cytokine-mediated immune pathways. In contrast, transcriptional responses at 3 dpi were limited, consistent with a silent phase of parasite dissemination. Despite the absence of detectable parasite DNA, placentomes showed modest interferon-associated responses and upregulation of DNA repair and cellular stress pathways. These changes coincided with marked suppression of cell-cycle progression and extracellular matrix remodeling alongside inhibition of angiogenesis and hypoxia pathways. Altogether, early disruption of placental vascular function and tissue remodeling may contribute to fetal loss. In summary, these findings provide new insights into early host responses to T. gondii infection in a pregnant host and identify molecular mechanisms that may predispose to early fetal death during ovine congenital toxoplasmosis.