Activation of innate sensing cGAS-STING pathway by Sindbis Virus

Abstract

Abstract The cGAS-STING pathway for cytosolic DNA sensing induces type I interferon response during the course of infection with DNA viruses, retroviruses or bacteria. In addition, cGAS detects cytosolic self-DNA, which could be resulted from the reactivation of endogenous retroviral elements or leaked from mitochondria or the nucleus under autoimmune conditions. Cytosolic RNA species can also serve as cGAS ligand in the form of DNA:RNA hybrid. However, the relevance of cGAS-STING pathway to RNA viruses remains unclear. In this study we report the activation of cGAS-STING pathway by Sindbis virus with a positive-sense single-stranded RNA genome. cGAS transcript was induced during Sindbis virus infection and this induction was independent of type I interferon signaling. Loss of either cGAS or STING augmented Sindbis virus replication and prevented viral induction of type I interferons, suggesting a possible role of cGAS-STING signaling pathway in the sensing of RNA viruses. Reconstitution of cGAS and STING in cGAS- and STING-null cells exhibited a protective effect against Sindbis virus infection. Analysis of cytosolic nucleic acid species enriched from Sindbis virus-infected cells indicated the presence of a cGAS ligand. Taken together, our findings reveal an unrecognized role of cGAS-STING pathway for cytosolic DNA sensing in RNA virus infection.