Zika virus NS4b protein inhibits antiviral innate immune response

SANCHEZ ALBERTI, ANDRÉS; NOLI TRUANT, SOFÍA; FERNÁNDEZ, MARISA M.; BIVONA, AUGUSTO E.; REDOLFI, DANIELA; MALCHIODI, EMILIO L.; SARRATEA, MARÍA B.; ANTONOGLOU, MARÍA B.; IANNANTUONO, LAURA

Kerry

Congreso; . Keystone Symposia on Positive-Strand RNA Viruses (E2); 2019

Keystone Symposia

Zika virus (ZIKV) has raised awareness after its association with congenital microcephaly and Guillain-Barré syndrome. At present, there is no approved vaccine or treatment against ZIKV infection; hence a better understanding of molecular interactions is needed. Type I interferons (IFN I) are key mediators in innate immunity against viral infections. At the cellular level, viral components can be sensed by intracellular pattern recognition receptors, activating interferon regulatory factor 3 (IRF3) and inducing the production of IFN I. However, many pathogens have evolved strategies to evade immune sensing favoring their survival. Among them, flaviviral non-structural proteins, needed for viral replication, are involved in host immune evasion. Here, we aimed to study the role of ZIKV NS4b protein in the inhibition of IFN I induction. For this purpose, we performed transfection assays with plasmid encoding recombinant ZIKV NS4b. Using RAW-Lucia ISG cells, an IFN reporter cell-line, we showed that cells with NS4b were able to reduce luciferase signals in a dose dependent manner compared to empty vectors. This reduction was maintained after treatment with TLR ligand, LPS, and STING agonist, c-di-AMP. We also conducted immunoprecipitation assays, confirming that NS4b interacts with TANK-binding kinase1 (TBK1), as recently reported. Furthermore, by confocal microscopy we were able to identify that ZIKV NS4b alone impairs IRF3 translocation to the nucleus in Hela cells. Our results suggest that ZIKV NS4b can be involved in disrupting TBK1/IRF3 cascade and considering the role of ZIKV NS4b in assembling the replication complex, we believe that it may be a promising target for antiviral drug development.