Alpha/Beta Interferon (IFN-α/β)-Independent Induction of IFN-λ1 (Interleukin-29) in Response to Hantaan Virus Infection

Type III interferons ([IFNs]IFN-λ and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-α/β). Like IFN-α/β, IFN-λ-expression can be induced by viruses, and it is believed that type I and III IFNs are regulated in the same manner. Hantaviruses are weak IFN-α/β inducers and have surprisingly been shown to activate IFN-α/β-independent IFN-stimulated gene (ISG) expression. Here, we show that in Hantaan virus (HTNV)-infected human epithelial A549 cells, induction of IFN-λ1 preceded induction of MxA and IFN-β by 12 and 24 h, respectively, and IFN-α was not induced at all. Furthermore, induction of IFN-λ1 and MxA was observed in HTNV-infected African green monkey epithelial Vero E6 cells, a cell line that cannot produce type I IFNs, clearly showing that HTNV can induce IFN-λ1 and ISGs in the complete absence of IFN-α/β. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-λ receptor, induction of MxA coincided in time with IFN-β-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-λ1 is dependent on replicating virus. Induction of both IFN-β and IFN-λ1 in A549 cells after poly(I:C)-stimulation was strongly inhibited in HTNV-infected cells, suggesting that HTNV can inhibit signaling pathways used to simultaneously activate types I and III IFNs. In conclusion, we show that HTNV can cause type I IFN-independent IFN-λ1 induction and IFN-λ1-specific ISG induction. Importantly, the results suggest the existence of specific signaling pathways that induce IFN-λ1 without simultaneous type I IFN induction during virus infection.