title: Alpha/beta interferon (IFN-alpha/beta)-independent induction of IFN-lambda1 (interleukin-29) in response to Hantaan virus infection.
abstract: Type III interferons ([IFNs] IFN-lambda and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-alpha/beta). Like IFN-alpha/beta, IFN-lambda-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-alpha/beta inducers and have surprisingly been shown to activate IFN-alpha/beta-independent IFN-stimulated gene (ISG) expression. Here, we show that in Hantaan virus (HTNV)-infected human epithelial A549 cells, induction of IFN-lambda1 preceded induction of MxA and IFN-beta by 12 and 24 h, respectively, and IFN-alpha was not induced at all. Furthermore, induction of IFN-lambda1 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-lambda1 and ISGs in the complete absence of IFN-alpha/beta. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-lambda receptor, induction of MxA coincided in time with IFN-beta-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-lambda1 is dependent on replicating virus. Induction of both IFN-beta and IFN-lambda1 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-lambda1 induction and IFN-lambda1-specific ISG induction. Importantly, the results suggest the existence of specific signaling pathways that induce IFN-lambda1 without simultaneous type I IFN induction during virus infection.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Stoltz
authors.forename: Jonas
authors.initials: J
authors.lastname: Klingström
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D018063:Hantaan virus / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000276:immunology; D015398:Signal Transduction; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda