Zika virus NS4b protein inhibits antiviral innate immune response

SARRATEA MB; SANCHEZ ALBERTI ANDRES; AUGUSTO E BIVONA; ANTONOGLOU MB; SOFIA NOLI TRUANT; DANIELA REDOLFI; LAURA IANNANTUONO; MARISA FERNDANDEZ; MALCHIODI EMILIO LUIS

Simposio; The Keystone Symposia: Positive-Strand RNA Viruses (E2); 2019

Type I interferons (IFN I) are key mediators in innate immunity against viral infections. At thecellular 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 hostimmune evasion. Here, we aimed to broaden the understanding of the role of Zika virus (ZIKV)NS4b protein in the inhibition of IFN I induction.For this purpose, we performed transfection assays with plasmid encoding recombinant ZIKVNS4b. Using RAW-Lucia ISG cells, an IFN reporter cell-line, we showed that cells with NS4bwere 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-diAMP. We also conducted immunoprecipitation assays, confirming that NS4b interacts withTANK-binding kinase1 (TBK1), as recently reported. Furthermore, by confocal microscopy wewere able to identify that ZIKV NS4b alone impairs IRF3 translocation to the nucleus in Helacells.ZIKV has raised awareness after its association with congenital microcephaly and Guillain-Barrésyndrome. At present, there is no approved vaccine or treatment against ZIKV infection; hencea better understanding of molecular interactions is needed. Our results suggest that ZIKV NS4bcan be involved in disrupting TBK1/IRF3 cascade. Because of this and the role of ZIKV NS4b inassembling the replication complex, we believe that it may be a promising target for antiviraldrug development.