ROP16 Promotes Epithelial-Mesenchymal Transition-Like Changes in Ocular Toxoplasmosis via STAT3 and TGF-β1 Pathways

Toxoplasmosis is a globally significant infectious disease, affecting approximately one-third of the world's population. Ocular toxoplasmosis (OT) is a major and vision-threatening clinical manifestation. However, its pathogenesis remains elusive, and effective targeted therapies are unavailable. This study demonstrates that Toxoplasma gondii infection induces epithelial-mesenchymal transition (EMT)-like changes in both human retinal pigment epithelial (RPE) cells (ARPE-19) and murine ocular tissues. Mechanistic investigations, employing rhoptry protein 16 (ROP16) knockout parasites and ROP16 overexpression models, revealed that the parasite-derived protein ROP16 promotes EMT-like changes by activating the host signal transducer and activator of transcription 3 (STAT3) and transforming growth factor β1 (TGF-β1) signaling pathway. Furthermore, pharmacological inhibition of STAT3 or TGF-β1 significantly attenuated EMT-like changes in vitro and ameliorated OT pathology in mice. In summary, our findings identify the ROP16-STAT3 and TGF-β1 pathways as a key regulatory pathway in OT pathogenesis, providing novel insights into the disease mechanism and suggesting STAT3 and TGF-β1 inhibitors as promising therapeutic candidates.