IMMUNOLOGY Alternate Pathway for Responding to RNA Viral Infection

Kato et al. report that mice lacking the ability to signal through the Toll-like receptor (TLR) pathway still stimulated expression of genes encoding interferons (IFNs) in fibroblasts in response to infection with RNA virus. In contrast, mouse embryo fibroblasts (MEFs) from mice deficient for retinoic acid-induced gene 1 (RIG-1) did not show increased expression of genes encoding IFN or genes regulated by IFN in response to infection with several different RNA viruses. In RIG-1-deficient MEFs, RNA virus infection failed to stimulate phosphorylation of signal transducer and activator of transcription 1 (STAT1) and dimerization of IFN regulatory factor 3 (IRF3), which are upstream events in the pathway that leads to increased IFN gene expression. Overexpression of TANK-binding kinase 1 (TBK1) and IKK-i [inhibitor of NF-B (IB) kinase (IKK)-related kinase] resulted in stimulation of an IFN-β reporter gene in the RIG-1^–/– MEFs, which suggests that the RIG-1 pathway involves these two kinases. Stimulation of both IFN-α and IFN-β production was impaired in one type of dendritic cell, conventional dendritic cells (cDCs), in the absence of RIG-1 but was not impaired by absence of TLR signaling (MyD88^–/–, TRIF^–/– cells). In contrast, IFN and interleukin-6 (IL-6) production was not impaired by deficiency of RIG-1, but was impaired by loss of TLR signaling in plasmacytoid dendritic cells (pDCs). Thus, there are two mechanisms for mounting an antiviral response to RNA viruses, a RIG-1 pathway that is active in fibroblasts and cDCs and a TLR pathway in other cells, including pDCs.

H. Kato, S. Sato, M. Yoneyama, M. Yamamoto, S. Uematsu, K. Matsui, T. Tsujimura, K. Takeda, T. Fujita, O. Takeuchi, S. Akira, Cell type-specific involvement of RIG-1 in antiviral response. Immunity 23, 19-28 (2005). [PubMed]

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