Susceptibility to Zika virus (ZIKV) infection is highly variable. While most seropositive individuals remain asymptomatic, approximately 18% develop symptoms that range from a mild rash to Guillain-Barré syndrome or microcephaly, and although less than 1% of neonates experience severe pathology, long-term effects may impact cognitive abilities. Like all known vector-borne flaviviruses, ZIKV must evade type I interferon (IFN) signaling to establish infection and cause disease. Recent evidence shows that ZIKV nonstructural protein 5 (NS5) targets the signal transducer and activator of transcription 2 (STAT2) for proteasomal degradation, thereby implicating STAT2 as a dominant restriction factor in ZIKV infection. Notably, mice are resistant to ZIKV as NS5 does not facilitate murine STAT2 degradation. To explain this variable pathology, we examined how naturally occurring mutations in STAT2 or its regulatory machinery impact ZIKV infection.
Individuals deficient for ubiquitin specific peptidase 18 (USP18), a negative regulator of IFN, or for IFN stimulated gene 15 (ISG15), a ubiquitin-like peptide that stabilizes USP18, are resistant to a broad spectrum of viral infections and exhibit elevated STAT2 levels for up to 6 days post exposure to IFN. Skin fibroblasts derived from ISG15-/- and USP18-/- individuals showed 1,000 – 100,000 fold stronger inhibition of ZIKV replication when pretreated with IFNα-2b, and retained more STAT2 than WT cells following infection. We also identified genetic variations in regions of STAT2 that likely alter the STAT2-NS5 interaction based on in silico damage prediction, species specificity of NS5 for human, but not murine, STAT2, and common targeting of STAT2 by NS5 from related flaviviruses. We therefore suggest that elevated STAT2 levels in ISG15-/- and USP18-/- cells inhibit ZIKV by creating a stoichiometric imbalance that favors IFN signaling despite NS5-mediated degradation of STAT2, and that heterogeneity within the STAT2 gene can explain differing levels of disease.