Abstract
BackgroundInfluenza A viruses are well characterized to antagonize type I IFN induction in infected mammalian cells. However, limited information is available for avian cells. It was hypothesised that avian influenza viruses (AIV) with distinct virulence may interact differently with the avian innate immune system. Therefore, the type I IFN responses induced by highly virulent and low virulent H5N1 AIV and reassortants thereof were analysed in chicken cells.ResultsThe highly pathogenic (HP) AIV A/chicken/Yamaguchi/7/04 (H5N1) (Yama) did not induce type I IFN in infected chicken HD-11 macrophage-like cells. This contrasted with an NS1 mutant Yama virus (Yama-NS1A144V) and with the attenuated H5N1 AIV A/duck/Hokkaido/Vac-1/04 (Vac) carrying the haemagglutinin (HA) of the Yama virus (Vac-Yama/HA), that both induced type I IFN in these cells. The substitution of the NS segment from Yama with that from Vac in the Yama backbone resulted in induction of type I IFN secretion in HD-11 cells. However, vice versa, the Yama NS segment did not prevent type I IFN induction by the Vac-Yama/HA virus. This was different with the PB1/PB2/PA segment reassortant Yama and Vac-Yama/HA viruses. Whereas the Yama virus with the Vac PB1/PB2/PA segments induced type I IFN in HD-11 cells, the Vac-Yama/HA virus with the Yama PB1/PB2/PA segments did not. As reported for mammalian cells, the expression of H5N1 PB2 inhibited the activation of the IFN-β promoter in chicken DF-1 fibroblast cells. Importantly, the Yama PB2 was more potent at inhibiting the IFN-β promoter than the Vac PB2.ConclusionsThe present study demonstrates that the NS1 protein and the polymerase complex of the HPAIV Yama act in concert to antagonize chicken type I IFN secretion in HD-11 cells. PB2 alone can also exert a partial inhibitory effect on type I IFN induction. In conclusion, the control of type I IFN induction by H5N1 HPAIV represents a complex phenotype that involves a particular viral gene constellation rather than a single viral protein. Collectively, these findings contribute to understand the high virulence of HPAIV H5N1 viruses observed in the chicken host.
Highlights
Influenza A viruses are well characterized to antagonize type I IFN induction in infected mammalian cells
A study conducted in ducks reported that the exchange of the NS segments between a high and a low virulent H5N1 virus had a minimal impact on pathogenicity [7]
The three HPAIV H5N1 strains, including Yama, Mongolia-3/ 05, and Turkey/Turkey/05 did not induce any type I IFN in embryonated chicken eggs 24 h after infection (Figure 1A). These findings contrasted with the LPAIV Vac and the HPAIV Vac-Yama/HA virus that induced approximately 50 U/ml type I IFN in the infected eggs
Summary
Influenza A viruses are well characterized to antagonize type I IFN induction in infected mammalian cells. Host cells express a broad repertoire of pattern recognition receptors (PRRs) to viral danger signals These include the of NS1 in the pathogenesis of avian influenza viruses (AIV) in chicken. Another report demonstrated enhanced virulence related to a deletion of 5 amino acids in the NS1 protein at positions 80 to 84, typically observed in recently emerged HPAIV H5N1 isolates [6]. PB2 protein inhibits the transcription of the IFN-b mRNA by interacting with the RLR-adaptor CARDIF ( known as MAVS, IPS-1, VISA) Along this line, it was reported that exchanging the PB1, PB2 and NP segments alters viral replication of H5N1 reassortant viruses in chicken and can modulate pathogenicity [15]. The PB2 and NP of H5N1 HPAIV are associated with increased pathogenicity in chicken [16]
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