**1. Introduction**

The recent epidemic caused by Zika virus (ZIKV), a mosquito-borne flavivirus, revealed the potential of the virus to inflict severe harm on infected individuals. Whereas infection is often asymptomatic or causes a self-limiting acute febrile illness in adults, it has been linked to multiple neurodevelopmental defects, including microcephaly, in newborns [1,2]. ZIKV has furthermore been associated with cases of Guillain–Barré syndrome, an autoimmune disease resulting in rapid-onset muscle weakness [3,4].

Experiments in cell culture and mice showed that ZIKV infection is controlled by type I interferons (IFNs), which represent the first line of defense against viral infections [5–8]. Type I IFNs are induced by pattern recognition receptors (PRRs) upon sensing of pathogen associated molecular patterns. For example, viral RNAs are detected by RIG-I-like receptors (RLRs) including retinoic acid-inducible gene I (RIG-I) and melanoma di fferentiation-associated gene 5 (MDA5). These PRRs then activate mitochondrial antiviral-signaling protein (MAVS). Downstream of MAVS, transcription factors such as

interferon regulatory factor 3 (IRF3) induce the expression and secretion of type I IFNs [9]. Binding of the secreted type I IFNs to their receptor in turn induces a signaling cascade involving signal transducer and activator of transcription (STAT) 1 and 2 hetero-dimerization that leads to the expression of interferon stimulated genes (ISGs). Some ISGs encode antiviral proteins that then restrict viral replication. Deficiency of PRRs increases ZIKV replication in human skin fibroblasts and mice lacking the type I IFN receptor (IFNAR), STAT2, MAVS or a combination of IRF transcription factors show higher viral replication and pathology [5,7,8,10–12]. ZIKV induces type I IFNs, and this is mainly dependent on MAVS, suggesting an important role of RIG-I and/or MDA5 in virus detection [7,13–18]. ZIKV antagonizes IFNAR signaling as viral replication is blocked only moderately if type I IFN is applied with or after ZIKV infection [19]. NS5, the RNA-dependent RNA polymerase that replicates the viral genome, is a potent viral antagonist of IFNAR signaling [6,13,20]. NS5 proteins from African and French Polynesian isolates were reported to interact with and target STAT2 for degradation [6,21]. Furthermore, NS5 prevents STAT1 and STAT2 phosphorylation [19,22,23].

Here, we explored the contribution of RIG-I and MDA5 to ZIKV sensing and found that RIG-I was the main sensor required to induce a protective type I IFN response upon virus infection. Loss of RIG-I-mediated type I IFN production in infected A549 cells led to the activation of apoptosis. We furthermore show that ZIKV NS5 not only interferes with IFNAR signaling, but additionally inhibited type I IFN induction upstream of type I IFN gene transcription.
