Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

In addition to DNA viruses, several viruses carrying singlestranded RNA (ssRNA) genomes have been reported to modulate STING and downstream signaling. Although this seems counterintuitive, published data describing different cellular mechanisms, provide a rationale for why some RNA viruses have evolved mechanisms to inhibit STING. First, RIG-I has been shown to interact with STING in a manner dependent on MAVS following activation by positive ssRNA viruses, thus amplifying the IFN production. 80 Second, Schoggins et al. 33 found lower basal expression of IFN-stimulated genes in cGAS − / − mice, and proposed that low-grade constitutive activation of this pathway sets the immunological tone in the organism. In support of this, cGAS − / − mice showed higher mortality compared with wild-type mice upon infection with the positive sense ssRNA virus West Nile virus. Finally, we identified that the virus cell membrane fusion induces induction of type I IFN expression in a STING-dependent but cGASindependent manner. 81 Using virus-like particles from HSV-1 lacking capsid and genomes as well as fusogenic cationic liposomes, we showed an induction of type I IFNs upon membrane fusion. 81 Coronaviruses are a big group of enveloped ssRNA with a positive sense genome. The swine virus Porcine epidemic diarrhea virus, infecting epithelial cells of the intestine, encodes a protease and deubiquitinase protein, named Papain-like protease 2 (PLP2). In addition to targeting RIG-I, PLP2 is able to interact directly with STING and reduce the ubiquitination status of the protein, resulting in reduced STING-dependent IFN expressions. 82 The STING-targeting mechanism is thought to be conserved in PLP-expressing coronaviruses, as PLP2-like proteins from human coronavirus (NL63) and severe acute respiratory syndrome virus (PLpro) respectively, both antagonize STING in a similar manner. 83 The protease NS2B3 from dengue virus is another STING targeting protein, with specific affinity for the human form of STING. The virus is enveloped with a non-segmented positive sense ssRNA genome, which normally induces low type I IFN levels, indicating an inhibitory evasion mechanism. The virus replication was shown to be more efficient in STING-depleted cells and this phenotype was explained by a protease-dependent cleavage of STING. The viral protease NS2B3 was found to interact with and cleave STING N-terminally, at the sequence LRRG. The LRRG sequence is not conserved in mice, and this lack of NS2B3 recognition sequence explains partly why the murine STING is not degraded by NS2B3. In addition to LRRG other regions in the STING molecule are necessary for efficient targeting by NS2B3, as a mutant form of murine STING, expressing the human LRRG sequence was still resistant to NS2B3-dependent cleavage. 84, 85 Finally, we have recently reported that the fusion peptide of the influenza A virus HA protein interacts with STING in a specific region localized close to the dimerization interphase of STING, and this prevents the dimerization of STING and downstream IFN production in response to membrane fusion but not cGAMP stimulation. 86 To our knowledge, Influenza A virus is the first example of a negative sense RNA virus, harboring a STING evasion mechanism. Collectively, STING dependent signaling pathways are also active during infection with RNA viruses. Therefore, this class of viruses has evolved means to dampen signaling by STING.