Suppression of dendritic cell necroptosis by pandemic influenza virus

Abstract

Abstract The public health risk of a new pandemic influenza virus (IAV) approaching the scope and mortality of the devastating 1918 strain makes it important to identify virus-host mechanisms unique to pandemic strains. Human dendritic cell infection by two different H1N1 seasonal IAV strains (1991 and 1999) induces widespread RNA degradation and programmed cell death beginning at 4 h after infection. Characteristic of necroptosis, the cell death showed nuclear condensation and fragmentation that was caspase independent and RIP3 kinase dependent. Notably, infection with the pandemic 1918 and 2009 H1N1 IAV strains did not induce dendritic cell RNA degradation and necroptosis. Furthermore, necroptosis induced in dendritic cells by poly I:C exposure was suppressed by concomitant infection with the pandemic 2009 IAV. These results indicate that infection with the pandemic viruses not only fails to induce the dendritic cell necroptosis seen with the seasonal IAV strains, but that it actively suppresses necroptosis. Virus chimera studies implicate the HA virus segment as mediating the necroptosis inhibition by the pandemic IAV strains. Necroptosis leads to the release of intracellular components which serve as danger associated molecular patterns (DAMP), making this a highly immunogenic cell death mechanism. Consistent with this view, we find that the suppression of virus-induced necroptosis by the pandemic IAV reduces T cell activation. These studies show that pandemic viruses are unique in suppressing a key immunological danger signal. The suppression of the generation of DAMPs from infected immune cells may contribute to the pathogenicity of pandemic H1N1 IAV viruses.