African swine fever virus B175L inhibits the type I interferon pathway by targeting STING and 2'3'-cGAMP.

Type I interferon (IFN)-mediated responses operate a pivotal role in the first line of host immune defense against viruses. Upon DNA virus infection, DNA sensing cyclic GMP-AMP synthase-STING signal pathway is a key event in the IFN-mediated antiviral response and also a target of viral immune evasion. African swine fever (ASF) is a highly contagious, cross-border viral disease that often confers fatalities in domestic and feral pigs of all ages. African swine fever virus (ASFV), a causative agent of ASF, is a nucleocytoplasmic large DNA virus that masks critical elements of host immune system by several encoded proteins. In this study, we report a novel immune evasion mechanism of ASFV B175L to block type I IFN signaling by targeting STING and 2'3'-cyclic GMP-AMP (2'3'-cGAMP). We found that ASFV B175L significantly inhibited the DNA virus-induced IFN-ß production and IFN-mediated signaling responses. The conserved zf-FCS motif of ASFV B175L competitively interacted with both cGAMP and the cyclic dinucleotide binding domain of STING. Remarkably, the R238 and Y240 amino acids of STING were crucial for interaction with ASFV B175L. Consequently, this interaction inhibits the interaction between cGAMP and STING, thereby inhibiting downstream signaling including STING polymerization and phosphorylation of TANK-binding kinase 1 and interferon regulatory factor 3 for antiviral signaling. Taken together, these results highlight the critical role of ASFV B175L in suppression of IFN responses and provide a new target to guide live-attenuated ASFV vaccine. [ABSTRACT FROM AUTHOR]