Background: Early cytokine dysregulation upon infection with highly pathogenic avian influenza viruses (HPAIV) is a major determinant of viral pathogenicity.Results: p38 MAPK controls HPAIV-induced gene expression by regulating interferon synthesis and subsequently interferon signaling, whereas its inhibition protects mice from lethal infection.Conclusion: p38 MAPK is crucial for the induction of hypercytokinemia upon infection.Significance: Targeting p38 MAPK is a promising approach for antiviral intervention.
Infections with highly pathogenic avian influenza viruses (HPAIV) in humans lead to systemic disease associated with cytokine storm and multiorgan failure. In this study we aimed to identify the role of monocytes for the host response to HPAIV infection. Using genome-wide microarray analysis, we surprisingly demonstrate a reduced immune response of human monocytes to HPAIV H5N1 compared to human influenza A viruses. In bioinformatic analyses we could reveal a potential role of the Rar-related orphan receptor alpha (RORa) for the gene expression pattern induced by H5N1. RORa is known as an inhibitor of NF-κB signaling. We provide evidence that in monocytes RORa is activated by H5N1, resulting in inhibited NF-κB signaling. Using murine Hoxb8-immortalized RORa-/-, monocytes rescued NF-κB signaling upon H5N1 infection, confirming the biological relevance of RORa as an H5N1-induced mediator of monocytic immunosuppression. In summary, our study reveals a novel RORa-dependent escape mechanism by which H5N1 prevents an effective inflammatory response of monocytes blocking NF-κB-dependent gene expression.
Since the last influenza pandemic in 2009, H1N1pdm has been introduced into the swine population in Europe where, in combination with swine influenza A virus (IAV) lineages, it started to generate a variety of reassortant viruses of unknown zoonotic risk for humans. To study these reassortment events, we isolated a wild swine lung cell clone (C22) susceptible to IAV infection. We established conditions for co-infection and passaging of H1N1pdm and swine avian-like H1N1. After 7 passages, we plaque-purified C22-adapted strains, characterized their genome composition by next-generation sequencing and analysed replication abilities in swine and human lung cell lines as well as in human lung tissue ex vivo.
Among C22-adapted viruses isolated from co-infection, we revealed reassortants carrying PB1/PA/NA or only PB1/PA from H1N1pdm. We also detected exclusively swine H1N1-derived strains. All isolates carried distinct mutations. As expected, adapted viruses reached higher titers compared to both parental strains in swine lung cells. Furthermore, all C22-adapted viruses were able to replicate in human lung A549 cells without any prior adaptation to the human host. Strikingly, all reassortants were able to infect and efficiently replicate in human lung tissue ex vivo, indicating that these viruses might pose a zoonotic risk.
To summarize, we successfully established an in vitro swine-like model to study reassortment and adaptation of IAVs currently circulating in swine. Our results indicate that our model might be a useful tool to prospectively evaluate the compatibility of different IAV strains to generate reassortants, which might represent a threat to the human population.
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