Flavivirus induces interferon-beta gene expression through a pathway involving RIG-I-dependent IRF-3 and PI3K-dependent NF-kappaB activation.
In this study, we found that infection with flaviviruses, such as Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2), leads to interferon-beta (IFN-beta) gene expression in a virus-replication- and de novo protein-synthesis-dependent manner. NF-kappaB activation is essential for IFN-beta induction in JEV- and DEN-2-infected cells. However, these two viruses seem to preferentially target different members of the interferon regulatory factor (IRF) family. The activation of constitutively expressed IRF-3, characterized by slower gel mobility, dimer formation, and nuclear translocation, is more evident in JEV-infected cells. Other members of the IRF family, such as IRF-1 and IRF-7 are also induced by DEN-2, but not by JEV infection. The upstream molecules responsible for IRF-3 and NF-kappaB activation were further studied. Evidently, a cellular RNA helicase, retinoic acid-inducible gene I (RIG-I), and a cellular kinase, phosphatidylinositol-3 kinase (PI3K), are required for flavivirus-induced IRF-3 and NF-kappaB activation, respectively. Therefore, we suggest that JEV and DEN-2 initiate the host innate immune response through a molecular mechanism involving RIG-I/IRF-3 and PI3K/NF-kappaB signaling pathways.
Chang
Tsung-Hsien
TH
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Liao
Ching-Len
CL
Lin
Yi-Ling
YL
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D003716:Dengue Virus / Q000502:physiology; D004664:Encephalitis Virus, Japanese / Q000502:physiology; D005416:Flavivirus / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020365:RNA Helicases / Q000378:metabolism*; D011971:Receptors, Immunologic; D014709:Vero Cells
D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D020365:RNA Helicases; D011971:Receptors, Immunologic; C452820:RIGI protein, human