Viral Evasion of STING-Mediated DNA Sensing and Stress Responses

The STING pathway is a key component of the host antimicrobial response, driving type I interferon production and inflammatory signaling. This process is efficient toward response to bacterial infection, and virus infection as many DNA and RNA viruses are counteracting its effects. It is activated by the aberrant presence of DNA in the cytoplasm. While primarily involved in defense against DNA viruses, this pathway can also be triggered during RNA virus infections, which may induce the release of mitochondrial DNA into the host cytosol. .

Several cytosolic DNA sensors activate the interferon response through STING, including ZBP1 , DDX41 , IFI16 and cGAS . The major pathway is mediated by cGAS-STING. cGAS detects aberrant cytoplasmic DNA and synthesizes cyclic GMP-AMP (cGAMP), which binds and activates STING. Activated STING dimerizes and oligomerizes, leading to the induction of two signaling branches: (i) type I interferon production via TBK1 and IRF3, and (ii) inflammatory responses via NF-?B activation.

IFI16 plays an essential antiviral role in nuclear viral DNA sensing. Herpesvirales do not expose their DNA in the cytoplasm, but still they induce IRF3-mediated antiviral response and this happens through IFI16.The way IFI16 distinguishes self nuclear DNA and foreign is under investigation, but the signaling seems to rely on IFI16 assembled in filaments on viral dsDNA.