Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

The cytosolic DNA sensors IFI16 and cGAS are activated in cells infected with DNA viruses. 1 Studies with different DNA viruses, including HSV-1 and CMV, have shown that viral genomic DNA associates with the DNA sensor IFI16, thus suggesting the foreign incoming genome to stimulate the DNA sensing machinery. 27, 35, 36 It has been demonstrated that viral genomic DNA is released into the cytosol upon infection, and this is preceded by K48-linked ubiquitination of capsid associated factors and subsequent proteosomal degradation of the viral capsid 27,37 ( Figure 2 ). Such studies suggest the viral genome to be the trigger of DNA-dependent immune responses. Other studies suggest that virus-induced cellular stress triggers release of mitochondrial DNA into the cytosol, which in turn activates the cGAS-STING pathway. Herpesviruses are reported to induce mitochondrial stress and through this mitochondrial DNA pathway stimulate cGAS activation. 38 The relative contribution of the different sources of DNA for the activation of the cGAS-STING pathway during viral infections remains to be characterized in details.