Viral evasion of DNA-stimulated innate immune responses

Abstract

Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.

Figure 1

Pattern recognition receptors sensing microbial DNA. Detection of DNA by AIM2 initiates the formation of the inflammasome complex with the adaptor protein ASC and Pro-caspase-1. Caspase-1 activation allows cleavage and maturation of the cytokines IL-1β and IL-18, which are secreted from the cell. TLR9 senses DNA in endosomes, resulting in MyD88-dependent activation of both NF-κB and IRF7 signaling pathways. cGAS binds cytosolic DNA and catalyzes the synthesis of the second messenger cGAMP, whereas IFI16 senses microbial DNA in both nuclear and cytosolic compartments. Both cGAS and IFI16 signal through the adaptor protein STING, resulting in STING dimerization and translocation from ER to ERGIC- and Golgi membrane structures. TBK1 and IRF3 recruitment to STING induces the phosphorylation and activation of IRF3. The active transcription factors NF-κB, IRF7 and IRF3 translocate to the nucleus and induce the transcription of type I IFN- and proinflammatory genes.

Figure 2

Virus-induced activation of cytosolic DNA sensors. Herpesvirus DNA is released into the cytosol as the virus capsid is K48-ubiquitinated and targeted for proteasomal degradation. The naked virus DNA is sensed by IFI16 and cGAS. Retroviruses express a reverse transcriptase enzyme and convert the RNA genome into DNA in the cytosol. More retrovirus replication intermediates, including the strong-stop (−) DNA, ssDNA stem loop structures and RNA:DNA hybrids, stimulate cGAS and IFI16. cGAMP is packed into particles from several viruses, including herpesviruses, pox viruses and retroviruses, and released into the cytosol upon viral entry to directly stimulate STING. Finally, virus-induced cellular stress can result in mitochondrial damage and release of mitochondrial DNA, which acts as a cGAS ligand. cGAS, IFI16 and STING activation initiates an IRF3-dependent transcription of type I IFN genes.

Figure 3

Evasion and inhibition of virus-induced type I IFN signaling. Virus-encoded proteins can inhibit DNA-stimulated immune responses at different levels, including (i) prevention of the exposure of viral DNA for the sensor proteins, (ii) inhibition of signaling from the DNA sensors to STING or (iii) blockage of signal transduction at the downstream level to prevent full activation of IRF3 resulting in decreased transcription of IFNs and IFN-stimulated genes. In addition to virus-encoded evasion proteins, retroviruses recruit cytosolic host proteins to the viral capsid to protect against sensing of replication intermediates by cytosolic nucleic acid sensors. Abbreviations: hAd5, human adenovirus 5; HPV18, human papillomavirus 18; POL, hepatitis B virus polymerase.