The Chicken cGAS–STING Pathway Exerts Interferon-Independent Antiviral Function via Cell Apoptosis

SIMPLE SUMMARY: The Interferon-independent antiviral function of stimulator of Interferon genes has recently received attention. However, the nature of this Interferon-independent antiviral function is not yet clear, although autophagy induced by stimulator of Interferon genes has been shown to mediate the antiviral activity of stimulator of Interferon genes. In birds, research is still nonexistent. Here, we first validated the antiviral activity of chicken stimulator of Interferon genes and determined the Interferon-independent antiviral activity of chicken stimulator of Interferon genes. Furthermore, it was found that autophagy induced by chicken stimulator of Interferon genes did not affect its antiviral activity. Finally, apoptosis induced by chicken stimulator of Interferon genes was involved in its antiviral process. Our results indicate that chicken stimulator of Interferon genes induces multiple signaling activities, which may be correlated during the antiviral process. This study demonstrates the complexity of the antiviral activity of chicken stimulator of Interferon genes and provides a unique approach for the study of antiviral activity other than that of Interferons. ABSTRACT: It has been recently recognized that the DNA sensing innate immune cGAS-STING pathway exerts an IFN-independent antiviral function; however, whether and how chicken STING (chSTING) exerts such an IFN-independent antiviral activity is still unknown. Here, we showed that chSTING exerts an antiviral activity in HEK293 cells and chicken cells, independent of IFN production. chSTING was able to trigger cell apoptosis and autophagy independently of IFN, and the apoptosis inhibitors, rather than autophagy inhibitors, could antagonize the antiviral function of chSTING, suggesting the involvement of apoptosis in IFN-independent antiviral function. In addition, chSTING lost its antiviral function in IRF7-knockout chicken macrophages, indicating that IRF7 is not only essential for the production of IFN, but also participates in the other activities of chSTING, such as the apoptosis. Collectively, our results showed that chSTING exerts an antiviral function independent of IFN, likely via apoptosis.