RIG-I, MDA5 and TLR3 Synergistically Play an Important Role in Restriction of Dengue Virus Infection

Abstract

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.

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

“…The anti-DV response was diminished when an antagonist was used to block the P2X 7 receptor (Fig. 3C), suggesting that full anti-DV activity by gd T cells requires activation checkpoints that involve two independent pathways of danger recognition: IRF-dependent pathways that lead to secretion of type I IFN (e.g., sensing of viral RNA by TLR3 and RIG-like receptors) (48,49) and the detection of extracellular ATP (e.g., released as a result of cell damage) with subsequent inflammasome activation (50). Reconstitution experiments demonstrated that CD16 + monocytes have a greater ability, on a per-cell basis, to augment the IFN-g response of gd T cells to DV-infected DC compared with CD14 + monocytes (Fig.…”

Mouse Embryonic Stem Cells Are Deficient in Type I Interferon Expression in Response to Viral Infections and Double-stranded RNA

“…In some cell types, polyIC can induce IFN␣/␤ via activation of TLR3 at the cell surface or in the endosomes (11,38,39) other responses that are similar to those evoked by viral infection via cytoplasmic dsRNA receptors (32,40). mESCs were unresponsive to polyIC that was directly added to the medium, likely due to the very low level expression of TLR3.…”

“…It is generally believed that MDA5 and RIG-I play primary roles in mediating viral RNA-induced IFN␣/␤ expression in the cytoplasm (11,39), although PKR also contributes to and modulates this process (13,14). Because MDA5 is expressed at a negligible level in mESCs, it is conceivable that PKR and/or RIG-I may mediate the effects of transfected polyIC.…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…25 We further examined the expression of pattern recognition receptors involved in DV-induced inflammatory cytokine releases, such as Toll-like receptors (TLRs), [26][27][28] …”