Monteagudo PL, et al. Differential modulation of innate immune responses in human primary cells by influenza A viruses carrying human or avian non-structural 1 proteins. J Virol. 2019 Oct 9. pii: JVI.00999-19
The influenza A virus (IAV) non-structural protein 1 (NS1) contributes to disease pathogenesis through the inhibition of host innate immune responses. Dendritic cells (DCs) release interferons (IFN), pro-inflammatory cytokines and promote the adaptive immunity upon viral infection. In order to characterize the strain-specific effects of IAV NS1 on human DC activation, we infected human DCs with a panel of recombinant viruses with the same backbone (A/Puerto Rico/08/1934) expressing different NS1 from human and avian origin. We found that these viruses induced a clearly distinct phenotype in DCs. Specifically, viruses expressing NS1 from human IAV (either H1N1 or H3N2) induced higher levels of expression of type I (IFNα and IFNβ) and type III (IFNλ1-3) than viruses expressing avian IAV NS1 proteins (H5N1, H7N9 and H7N2), but the differences observed in the expression of pro-inflammatory cytokines like TNFα or IL-6 were not significant. In addition, using Imaging Flow Cytometry, we found that human and avian NS1 segregate based on their subcellular trafficking dynamics, which might be associated with the different innate immune profile induced in DCs by viruses expressing those NS1 proteins. Innate immune responses induced by our panel of IAV recombinant viruses were also characterized in Normal Human Bronchial Epithelial cells and the results were consistent with those in DCs. Altogether, our results reveal an increased ability of NS1 from avian viruses to antagonize innate immune responses in human primary cells as compared to NS1 from human viruses which could contribute to the severe disease induced by avian IAV in humans.Importance Influenza A viruses (IAV) cause seasonal epidemics which result in an important health and economic burden. Wild aquatic birds are the natural host of IAV. However, IAV can infect diverse hosts, including humans, domestic poultry, pigs, and others. IAV circulating in animals occasionally cross the species barrier infecting humans, which results in mild to very severe disease. In some cases, these viruses can acquire the ability to transmit among humans and initiate a pandemic. The non-structural (NS) 1 protein of IAV is an important antagonist of the innate immune response. In this study, using recombinant viruses and primary human cells, we show that NS1 proteins from human and avian hosts show intrinsic differences in the modulation of the innate immunity in human dendritic cells and epithelial cells, as well as different cellular localization dynamics in infected cells.
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