RIG-I Signaling Is Essential for Influenza B Virus-Induced Rapid Interferon Gene Expression

Abstract

Influenza B virus causes annual epidemics and, along with influenza A virus, accounts for substantial disease and economic burden throughout the world. Influenza B virus infects only humans and some marine mammals and is not responsible for pandemics, possibly due to a very low frequency of reassortment and a lower evolutionary rate than that of influenza A virus. Influenza B virus has been less studied than influenza A virus, and thus, a Influenza A and B viruses are important respiratory pathogens and cause seasonal epidemics with an estimated 250,000 to 500,000 deaths annually. Influenza A and B viruses are structurally similar: they are negative-sense RNA viruses with a singlestranded segmented genome. The genome is structured in eight viral ribonucleoprotein (vRNP) complexes where the singlestranded RNA (ssRNA) is associated with multiple nucleoprotein (NP) molecules and a polymerase complex consisting of the PB1, PB2, and PA proteins (1). The vRNP complexes are packaged in a matrix protein shell surrounded by a host-derived lipid envelope in which the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) are embedded. Influenza viruses bind to sialic acids on cell surface glycoproteins and enter the cells mainly via clathrin-mediated endocytosis but also by macropinocytosis and clathrin-independent entry pathways (2, 3). Influenza viruses take advantage of the host endocytic pathway; a reduction of pH during the maturation of endosomes induces a conformational change in viral HA molecules and triggers fusion between viral and endosomal membranes. Fusion is followed by the uncoating of the capsid by M1 dissociation due to acidification of the virion via the M2 ion channel protein. This results in the release of vRNPs into the cytosol. The influenza virus genome is then imported into the nucleus for transcription and replication of viral genes. Primary transcription of the viral genome is triggered by the virion-associated polymerase protein complex, which leads to the translation of early viral proteins in the cell cytoplasm. Newly synthesized polymerase, NP, and NS1 proteins are transported into the nucleus, where they initiate and regulate the replication and synthesis of cRNA and viral RNA (vRNA) molecules, followed by secondary rounds of transcription. At later stages of infection, new vRNP complexes are packaged in the nucleus, followed by M1-and nuclear export protein (NEP)-regulated export of vRNPs into the cytoplasm. Here they associate with viral envelope glycoproteins HA and NA on the plasma membrane, leading to budding of the newly formed viral particles (4).

Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection

“…These results indicate that RIG-I is essential for the activation of transcriptional factors and cytokine production during the early stage of influenza B virus infection. Previous studies reported similar results (29), suggesting that RIG-I signaling plays crucial roles against influenza B virus infection.…”

“…We postulated that the activation of the innate immune response by influenza B virus infection protected the host cells from superinfection. Given that viral infections elicit the activation of IFNs and proinflammatory factors and that influenza B virus induces IFNs directly upon entry into human primary monocyte-derived dendritic cells (27)(28)(29), we tested the cytokine expression levels induced by influenza B virus in A549 cells, and the transcriptional levels of viral NP and NS1 protein were also analyzed. As shown in Fig.…”

Type I interferon antagonistic properties of influenza B virus polymerase proteins

“…5 0 ppp-dsRNA is the specific ligand for RIG-I to trigger activation of IRF3, resulting in the release of IFNβ (Hornung et al, 2006;Mäkelä et al, 2015). To induce type I IFN expression, commercially available 5 0 -triphosphate RNA was used as a stimulus in comparison with a negative-control-5 0 ppp-dsRNA (InvivoGen).…”

Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

“…, and IBV B/Shandong/7/97 were grown in allantoic cavities of 11-day-old embryonated chicken eggs at ϩ36°C for 3 days. Virus titers from supernatant samples were determined by a plaque assay in MDCK cells, as previously described (41,69,70). The MOI is given according to the titers determined in the MDCK cells (41).…”

“…UV irradiations of the stock viruses were performed at 600 mJ of UV light before the viruses were added to the cells. The infectivity of IAVs was completely destroyed by the dose of UV light used (69). At 21 h after transfection, the cells were infected with either UV-irradiated (control) or live IAVs for different periods of time, as described in the figure legends.…”