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ABSTRACT Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although infection is associated with severe morbidity in some individuals, the molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was critically required for type I interferon (IFN) induction in response to VZV infection. Viral gene overexpression screening identified the essential VZV tegument protein ORF9 as a novel antagonist of DNA sensing via cGAS. Ectopically as well as virally expressed ORF9 bound to endogenous cGAS. Confocal microscopy revealed co-localisation of cGAS and ORF9, which blocked the type I IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system. Our data further suggest that ORF9 inhibited the production of cGAMP by cGAS. Taken together, our work highlights the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identified an immune antagonist encoded by VZV that directly interferes with DNA sensing via cGAS.

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