ID: 28: Influenza B virus entry induces RIG-I-dependent rapid interferon gene expression

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Macrophages and dendritic cells are equipped with a plethora of pattern recognition receptors which are activated by microbial structural components and genetic material. Many of the receptors sense the presence of viral RNA and DNA and activate signaling cascades leading to the induction of interferons, other cytokines and antiviral proteins. In the present study we have analyzed immediate early activation of innate immunity by influenza B virus infection in human monocyte-derived dendritic cells (moDC) and macrophages. Influenza viruses enter the cell mainly via clathrin-mediated endocytosis followed by the release of the vRNP complexes into the cytoplasm and transport into the nucleus where viral transcription and replication is initiated. We have shown before that influenza A virus induces interferon responses in human moDCs only after replication of the viral genome whereas influenza B virus triggers IFN gene expression prior to any transcription or replication of the virus. Here we show that in human macrophages influenza B virus activates IRF3 phosphorylation and nuclear accumulation after the fusion of the viral membrane with the endosomal membranes in a process where no viral transcription or synthesis of influenza B virus proteins is needed. Experiments with knock-out mouse embryonic fibroblasts lacking RIG-I or/and MDA5 receptors show that influenza B virus-induced early activation of IRF3 is RIG-I dependent. Revealing the molecular mechanisms of influenza virus and host cell interactions may lead to better means to control influenza virus infections in the human host.