Abstract
Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Stinggt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Stinggt/gt mice was significantly impaired. Stinggt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15-/-T. gondii was more virulent and caused higher mortality of WT mice but not Stinggt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.
Highlights
Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals
We found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses
TLR11 and TLR12 form a heterodimer in murine dendritic cells (DC) after sensing Profilin and activate adaptor protein MyD88 to initiate downstream signaling for defense against T. gondii [5]
Summary
The cGAS/STING axis recognizes cytoplasmic DNA and triggers innate immune responses. Here, we investigated the role of STING in host defense against the infection of T. gondii. GRA15Ϫ/Ϫ parasite infection caused more severe mortality of mice These results suggested that GRA15 is required for competent induction of innate immune responses. IFN enhancement was observed in RELAdeficient cells (Fig. S3D) These results suggested that GRA15 activates NF-B–independent innate immune signaling, which contributes to type I IFN enhancement. The RNA-seq analysis showed that GRA15 induced the expression of the genes involved in innate immune responses, defense response to virus, and herpes simplex infection (Fig. 3E) Induction of these ISGs by GRA15, including GBP3, was significantly attenuated in STING-deficient macrophages (Fig. 3F). The results showed that GRA15 was not able to enhance IFN induction by cGAS/STING without TRAF proteins (Fig. 6, B and C). TRAF proteins play a vital role in cGAS/STING/GRA15-mediated immune response by bridging the interaction between GRA15 and STING
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