Predominant role of IPS-1 over TRIF adaptor proteins in early innate immune response against Zika virus in mice.

Toll-like receptors and RNA helicases are involved in the control of RNA virus infection through production of type I interferons (IFNs). To delineate the relative contributions of these signalling pathways in the innate immune response and the control of Zika virus (ZIKV) pathogenesis, the impact of a deficiency in TRIF and/or IPS-1 adaptor proteins was investigated in mice. Mice were infected intravenously with ZIKV and monitored for clinical signs for 14 days. Groups of mice were sacrificed on days 1, 3 and 7 post-infection (p.i.) and viral RNA was measured by digital droplet PCR in serum, spleen, brain and eyes. Some mice were sacrificed at 12 h p.i. for determination of the levels of IFN-α/-β (ELISA), cytokines/chemokines (Luminex) and total/phosphorylated IRF3 and IRF7 (Western blotting). All groups of mice infected with ZIKV exhibited no clinical signs of infection. However, IPS-1-/- and TRIF-/-xIPS-1-/- mice developed higher viraemia than WT and TRIF-/- groups on days 1, 3 and 7. TRIF-/-xIPS-1-/- mice presented higher viral RNA levels in spleen, brain and eyes over time than TRIF-/-, IPS-1-/- and WT groups. At 12 h, IFN-α/-β and cytokine/chemokine levels in spleen were significantly decreased in IPS-1-/- and TRIF-/-xIPS-1-/- compared to WT and TRIF-/-. On day 1 p.i., IFN-β levels were significantly reduced in spleen of TRIF-/-xIPS-1-/- mice compared to all other groups. These data suggest that IPS-1 plays a more important role than TRIF in the early type I IFN response and that both IPS-1 and TRIF are involved at later stages of ZIKV infection.