IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein.
Influenza A virus causes epidemics of respiratory diseases in humans leading to thousands of death annually. One of its major virulence factors, the non-structural protein 1 (NS1), exhibits interferon-antagonistic properties. While epithelial cells of the respiratory tract are the primary targets of influenza virus, the virus-sensing mechanisms in these cells eventually leading to IFNbeta production are incompletely understood. Here we show that infection of epithelial cells with NS1-deficient influenza A virus upregulated expression of two molecules that have been previously implicated in sensing of RNA viruses, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5). Gene silencing and overexpression experiments demonstrated that RIG-I, its adapter interferon-beta promoter stimulator 1 (IPS-1) and interferon-regulated factor 3 (IRF3) were involved in influenza A virus-mediated production of the antiviral IFNbeta. In addition, we showed that the NS1 protein is capable to inhibit the RIG-I-induced signalling, a mechanism which corresponded to the observation that only NS1-deficient but not the wild-type virus induced high-level production of IFNbeta. In conclusion, we demonstrated a critical involvement of RIG-I, IPS-1 and IRF3 in influenza A virus infection of epithelial cells.
Opitz
Bastian
B
Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. bastian.opitz@charite.de
Rejaibi
Amira
A
Dauber
Bianca
B
Eckhard
Jamina
J
Vinzing
Maya
M
Schmeck
Bernd
B
Hippenstiel
Stefan
S
Suttorp
Norbert
N
Wolff
Thorsten
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D015151:Immunoblotting; D009980:Influenza A virus / Q000235:genetics / Q000254:growth & development*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000502:physiology; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1