Highly Pathogenic Influenza Viruses Inhibit Inflammatory Response in Monocytes via Activation of Rar-Related Orphan Receptor ROR alpha

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 (ROR alpha) for the gene expression pattern induced by H5N1. ROR alpha is known as an inhibitor of NF-kappa B signaling. We provide evidence that in monocytes ROR alpha, is activated by H5N1, resulting in inhibited NF-kappa B signaling. Using murine Hoxb8-immortalized ROR alpha(-/-), monocytes rescued NF-kappa B signaling upon H5N1 infection, confirming the biological relevance of ROR alpha as an H5N1-induced mediator of monocytic immunosuppression. In summary, our study reveals a novel ROR alpha-dependent escape mechanism by which H5N1 prevents an effective inflammatory response of monocytes blocking NF kappa B-dependent gene expression. Copyright (c) 2013 S. Karger AG, Basel