Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

IFI16 is predominantly nuclear, but a small pool of IFI16 is cytoplasmic and has been demonstrated to co-localize with herpes simplex virus (HSV)-1 genomic DNA in the cytoplasm upon infection. 27 IFI16 binds the DNA via two HIN domains, allowing the formation of filamentous oligomers on the DNA molecule, which is thought to facilitate signaling through STING and the induction of type I IFN. [27] [28] [29] One study has shown IFI16 to have higher affinity for longer, naked DNA fragments (4150 bp) than short fragments. As nuclear self-DNA is bound by histones, the IFI16 affinity for longer DNA fragments could potentially represent a mechanism to discriminate between self-and non-self DNA. 29 At present it is not explained how IFI16 mediates signaling, although there are papers to suggest that IFI16 and cGAS act in the same pathway. 30, 31 Experimental in vivo work in mice has demonstrated the importance of AIM2 in the early control of murine cytomegalovirus (CMV) after intraperitoneal infection, acting through a mechanism dependent on induction of IL-18 and stimulation of type II IFN production by natural killer cells. 32 Likewise, cGAS is essential for control of infections with HSV-1 (intravenous infection), murine gammaherpesvirus 68 (MHV68) (intraperitoneal infection), and vaccinia virus (intranasal infection), and this is believed to be dependent on induction of type I IFN. 33, 34 STING − / − mice were found to display elevated mortality rate after intravenous HSV-1 infection compared with wildtype mice, and the virus replicated more efficiently in the brain of STING-deficient mice. Importantly, these signs correlated with no detectable type I IFN in the blood of infected STINGdeficient animals. 23 In agreement with this, HSV-1 did not induce detectable levels of type I IFN in STING − / − MEF cells and bone-marrow-derived macrophages. 23 Interestingly, this phenotype was largely identical in cGAS − / − mice after HSV-1 infection through the same route, suggesting that potential alternative functions of these proteins are not central in host defense against HSV-1. 34