The cleavage of STING by NS2B3 during flavivirus immune evasion might be a common feature
Zhen Wu1, Shun Chen1*, Suresh Mahalingam2, Anchun Cheng1*
1Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; 2Institute for Glycomics, Griffith University, Gold Coast, Australia
Duck Tembusu virus (TMUV, genus Flavivirus, family Flaviviridae) is a novel flavivirus genus which has caused severe disease in ducks and huge economic losses in China since 2009. Zika virus (ZIKV) and Dengue virus (DENV) are emerging important human pathogen, and we aim to find some new common features with DTMUV including the virus replication and interaction with hosts.
In this study, we screened DTMUV-encoded nonstructural proteins using reporter assays and found that DTMUV NS2B3 markedly suppressed NDV-triggered IFN-β expression by inhibiting retinoic acid-inducible gene I-like receptor signaling, and the mechanisms of the inhibition of innate immune responses is by cleave 'RG' at the amino acid position 84/85 in the duck stimulator of interferon genes (STING) molecule. Meanwhile, the co-transfection of Japanese encephalitis virus (JEV), or ZIKV, or DENV NS2B3 with duck STING or with human STING have been done. ZIKV and DENV NS2B3 are able to cleave duck STING, and TMUV NS2B3 cleaves human STING which further inhibits the production of duck IFNβ and human IFNβ, respectively. However, none of DENV, ZIKV, or TMUV NS2B3 can cleave the mouse STING. This reduces the status of mice as a model organism for studying innate immunity. Previous studies have shown that DENV does not cleave STING of primates that serve as their reservoirs, and that primates have an innate immune response to DENV infection that is significantly different from humans, and DENV, ZIKV, and TMUV NS2B3 on the mutual cleave of human STING and duck STING prompted us to speculate that duck may as a identify animals that could be strong a candidate for future research innate immune response into DENV and ZIKV. We introduced mutations in the catalytic triad of DENV, ZIKV and DTMUV infection clone in the protease region, S135A, that have been reported to impair protease activity, and generated a map of cis- and trans-acting elements in RNA replication for the nonstructural coding region of the flavivirus genome for complementation analysis, to lay the foundation for study polyprotein processing and viral replication mechanism of Flaviviruses and construction of chimeric viruses for the next step.