A tunable immune-evasion function of Zika virus NS5 governs viral fitness and pathogenesis

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Abstract
Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Zika virus (ZIKV) and dengue virus evade this pathway through nonstructural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune-evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multistep mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5 L162G exhibited markedly reduced viral loads and disease. In pregnant human STAT2 knock-in mice, the mutant also reduced placental and fetal viral burdens and adverse pregnancy outcomes. Notably, infection with ZIKV-NS5 L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune-evasion, viral fitness, and pathogenesis and highlight disruption of NS5–STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation.
Funding Information
  • National Key Research and Development Program of China (2023YFC2305900)
  • National Natural Science Foundation of China (82241077)
  • National Natural Science Foundation of China (82341084)
  • National Natural Science Foundation of China (82272302)
  • Tsinghua University Dushi Program (20251080029)

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