Abstract
Influenza infection is a major cause of morbidity and mortality. Retinoic acid-inducible gene I (RIG-I) is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focuses on the hypothesis that pandemic H1N1/09 influenza virus alters the influenza-induced proinflammatory response and suppresses host antiviral activity. We first compared the innate response to a clinical isolate of influenza A(H1N1)pdm09 virus, OK/09, a clinical isolate of seasonal H3N2 virus, OK/06, and to a laboratory adapted seasonal H1N1 virus, PR8, using a unique human lung organ culture model. Exposure of human lung tissue to either pandemic or seasonal influenza virus resulted in infection and replication in alveolar epithelial cells. Pandemic virus induces a diminished RIG-I mRNA and antiviral cytokine response than seasonal virus in human lung. The suppression of antiviral response and RIG-I mRNA expression was confirmed at the protein level by ELISA and western blot. We performed a time course of RIG-I and interferon-β (IFN-β) mRNA induction by the two viruses. RIG-I and IFN-β induction by OK/09 was of lower amplitude and shorter duration than that caused by PR8. In contrast, the pandemic virus OK/09 caused similar induction of proinflammatory cytokines, IL-8 and IL-6, at both the transcriptional and translational level as PR8 in human lung. Differential antiviral responses did not appear to be due to a difference in cellular infectivity as immunohistochemistry showed that both viruses infected alveolar macrophages and epithelial cells. These findings show that influenza A(H1N1)pdm09 virus suppresses anti-viral immune responses in infected human lung through inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I, though proinflammatory cytokine induction was unaltered. This immunosuppression of the host antiviral response by pandemic virus may have contributed to the more serious lung infections that occurred in the H1N1 pandemic of 2009.
Highlights
In 2009, a global outbreak caused by the novel pandemic H1N1 influenza virus spread to numerous countries and infected over 300,000 individuals with at least 16,000 confirmed human deaths worldwide (WHO)
We found that pandemic H1N1 virus suppresses Retinoic acid-inducible gene I (RIG-I) induction and has an immunosuppressant effect on antiviral immune responses in infected human lung, which may contribute to the increased lung pathogenicity of this pandemic strain
Figures d-f of 1A are corresponding bright-field images which demonstrate that lung architecture is preserved during the experiment the human lung slices support infection during exposure to both influenza virus strains
Summary
In 2009, a global outbreak caused by the novel pandemic H1N1 influenza virus spread to numerous countries and infected over 300,000 individuals with at least 16,000 confirmed human deaths worldwide (WHO). The influenza A(H1N1)pdm virus originated from two swine influenza A virus strains. The new virus has gene segments from a North American H3N2 triple reassortment, classical swine H1N1 lineage, and a Eurasian avian-like swine H1N1 virus. Sequence analysis of this new pandemic virus revealed that hemagglutinin (HA), nucleoprotein (NP), and NS gene segments were derived from the classical swine viruses via the triple reassortant. The PB1, PB2, and PA gene segments were from the North American H3N2 triple reassortment lineage. The NA and M segments originated from the Eurasian swine virus lineage. The influenza A(H1N1)pdm virus is genetically and antigenically distinct from previous seasonal human influenza A H1N1 viruses. The seasonal influenza vaccines provided little protection [3]
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