Placenta-derived interferon-stimulated gene 20 controls ZIKA virus infection

Zika virus is a positive-sense single-stranded RNA virus, which can be transmitted across the placenta and has adverse effects on fetal development during pregnancy. The severity of these complications highlights the importance of prevention and treatment. However, no vaccines or drugs are currently available. In this study, we characterize the IFNβ-mediated anti-viral response in trophoblast cells in order to identify critical components that are necessary for the successful control of viral replication and determine whether components of the IFN-induced response can be used as a replacement therapy for ZIKA virus infection during pregnancy. We identify and characterize interferon-stimulated gene 20 (ISG20) as playing a central role in controlling Zika virus infection in trophoblast cells and successfully establish a recombinant ISG20-Fc protein that effectively decreases viral titers in vitro and in vivo by maintaining its exonuclease activity and displaying potential immune modulatory functions. Recombinant ISG20-Fc has thus the potential to be further developed as an anti-viral treatment against ZIKA viral infection in high-risk populations, particularly in pregnant women. Synopsis ISG20 is the key exonuclease to inhibit ZIKA viral replication in trophoblast cells via the degradation of viral RNA. A recombinant ISG20-Fc protein reduces ZIKA infection in vitro and in vivo . In first-trimester trophoblast cells ZIKA infection significantly induces expression of IFNβ and downstream anti-viral ISGs. Lack of ISG20 renders the trophoblast cells more susceptible to ZIKA infection. Recombinant ISG20-Fc protein retains exonuclease activity and degrades ZIKA viral RNA and HSV-2 DNA. rISG20-Fc treatment reduces pregnancy loss and viral titers in maternal serum and fetal brain in ZIKA-infected mice. Graphical Abstract ISG20 is the key exonuclease to inhibit ZIKA viral replication in trophoblast cells via the degradation of viral RNA. A recombinant ISG20-Fc protein reduces ZIKA infection in vitro and in vivo .