RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection

• Published in: PLoS neglected tropical diseases Vol. 5; no. 1; p. e926
• Main Authors: Nasirudeen, A M A, Wong, Hui Hui, Thien, Peiling, Xu, Shengli, Lam, Kong-Peng, Liu, Ding Xiang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.01.2011; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Cells, Cultured; Cytokines; DEAD Box Protein 58; DEAD-box RNA Helicases - immunology; DEAD-box RNA Helicases - metabolism; Dengue - immunology; Dengue - pathology; Dengue fever; Dengue virus; Dengue Virus - immunology; Dengue Virus - pathogenicity; Dengue virus type 1; Gene Silencing; Genes; Genetic engineering; Hepatitis; Hepatocytes - virology; Humans; Immune response; Immune system; Immunology/Cellular Microbiology and Pathogenesis; Immunology/Immune Response; Immunology/Immunity to Infections; Immunology/Innate Immunity; Infections; Interferon; Interferon-Induced Helicase, IFIH1; Interferons - immunology; Interferons - metabolism; Macrophages - virology; Melanoma; Mice; Mice, Inbred C57BL; Microbiology/Cellular Microbiology and Pathogenesis; Microbiology/Innate Immunity; Pattern recognition; Receptors, Immunologic; Reverse Transcriptase Polymerase Chain Reaction; Sensors; Toll-Like Receptor 3 - immunology; Toll-Like Receptor 3 - metabolism; Tropical diseases; Vector-borne diseases; Viral diseases; Viral infections; Viruses; West Nile virus; Singapore; Asia; Toll-Like Receptor 3; DEAD-box RNA Helicases; Interferons; Dengue; Humans; Mice, Inbred C57BL; Cells, Cultured; Gene Silencing; Macrophages; Reverse Transcriptase Polymerase Chain Reaction; Dengue Virus; Animals; Hepatocytes; Mice; Apoptosis
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0000926

Dengue virus (DV) infection is one of the most common mosquito-borne viral diseases in the world. The innate immune system is important for the early detection of virus and for mounting a cascade of defense measures which include the production of type 1 interferon (IFN). Hence, a thorough understanding of the innate immune response during DV infection would be essential for our understanding of the DV pathogenesis. A recent application of the microarray to dengue virus type 1 (DV1) infected lung carcinoma cells revealed the increased expression of both extracellular and cytoplasmic pattern recognition receptors; retinoic acid inducible gene-I (RIG-I), melanoma differentiation associated gene-5 (MDA-5) and Toll-like receptor-3 (TLR3). These intracellular RNA sensors were previously reported to sense DV infection in different cells. In this study, we show that they are collectively involved in initiating an effective IFN production against DV. Cells silenced for these genes were highly susceptible to DV infection. RIG-I and MDA5 knockdown HUH-7 cells and TLR3 knockout macrophages were highly susceptible to DV infection. When cells were silenced for only RIG-I and MDA5 (but not TLR3), substantial production of IFN-β was observed upon virus infection and vice versa. High susceptibility to virus infection led to ER-stress induced apoptosis in HUH-7 cells. Collectively, our studies demonstrate that the intracellular RNA virus sensors (RIG-I, MDA5 and TLR3) are activated upon DV infection and are essential for host defense against the virus.