Toxoplasma gondii GRA3 activates interferon-stimulated genes and STAT6 by the cGAS-STING pathway to promote parasite proliferation

Toxoplasma gondii is an opportunistic protozoan parasite that can establish latent infections in humans, causing toxoplasmosis in immunocompromised individuals. Type I interferons (IFN-I), particularly IFN-β, are critical for controlling Toxoplasma gondii infection, but the parasite has evolved various strategies to manipulate the host immune response. Interferon regulatory factor 3 (IRF3) is a key transcription factor that regulates the expression of antiviral genes, including IFN-I and ISGs. Unlike IFN-β, IRF3-activated ISG56 can enhance T. gondii proliferation. Furthermore, STAT6 activation has also been reported to promote the proliferation of Toxoplasma gondii . In this study, we found that GRA3 is highly expressed in the less virulent ME49 strain. Furthermore, we discovered that GRA3 interacted with STING to activate the cGAS/STING pathway. This interaction promotes STING oligomerization and the nuclear translocation of phosphorylated-IRF3, which in turn enhances IFN-β production. GRA3 in ME49 tachyzoites promoted both IRF3-mediated ISG56 expression and STAT6 phosphorylation, thereby enhancing the proliferation of these less virulent parasites. Interestingly, GRA3 enhances parasite proliferation via a mechanism mediated by ISG56 and STAT6, rather than by IFN-β. This study highlights how less virulent strains modulate host immunity to promote T. gondii survival and replication, establish latent infections, and ultimately achieve widespread dissemination in humans.