LAUSR

Zika virus (ZIKV) is a mosquito-transmitted emerging Flavivirus causing the Guillain-Barré syndrome and microcephaly in adults and fetuses, respectively. Since ZIKV was first isolated in 1947, severe outbreaks have occurred at various places worldwide, including in the Yap Island in 2007, in the French Polynesia in 2013, and in Brazil in 2015. Although incidences of ZIKV infection and dissemination have drastically increased, the mechanisms underlying the pathogenesis of ZIKV and ZIKV related-diseases have not been sufficiently studied. In addition, despite extensive research, the exact roles of individual ZIKV genes on the viral evasion of host innate immune responses remain elusive. Besides, it is still possible that more than one ZIKV-encoded protein may negatively affect type I interferon (IFN) induction. Hence, in this study, we aimed to determine the modulations of the IFN promoter activity, induced by the MDA5/RIG-I signaling pathway, by over-expressing individual ZIKV genes. Our results show that two nonstructural proteins, NS2A and NS4A, significantly down-regulated the promoter activity of IFN-β by inhibiting multiple signaling molecules involved in the activation of IFN-β. Interestingly, while NS2A suppressed both full-length and constitutively active RIG-I, NS4A had inhibitory activity only on full-length RIG-I. In addition, while NS2A inhibited all forms of IRF3 (full-length, regulatory domain-deficient, and constitutively active), NS4A could not inhibit constitutively active IRF3-5D. Taken together, our results showed that NS2A and NS4A play major roles as antagonists of MDA5/RIG-I-mediated IFN-β induction and more importantly, those two viral proteins seem to inhibit induction of type I IFN responses in differential mechanisms. We believe this study expands our understanding regarding the mechanisms via which ZIKV controls innate immune responses and may pave way to development of ZIKV-specific therapeutics.