Identification and characterization of specific amino acid residues in the NS1 protein that facilitated viral replication of avian influenza viruses in mammalian host

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KanraiPumaree_2015_04_21.pdf (4.66 MB)

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2015

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DOI:
http://dx.doi.org/10.22029/jlupub-10330

Abstract

Recently, it was shown that the NS-segment of the avian influenza virus strain A/Goose/Guangdong/1/1996 (GD, H5N1) promotes replication and increases pathogenicity of the strictly avian strain A/FPV/Rostock/34 (FPV, H7N1) in mammalian cells and mice, whereas the NS-segment of A/Mallard/NL/12/2000 (MA, H7N3) impaired FPV replication in mammalian cells. The NS1 proteins of GD and Ma differ only by eight amino acids. Nevertheless, the critical genetic differences were not yet identified. In this report, I demonstrate that the specific amino acid changes D74N and/or P3S+R41K+D74N in the NS1-MA protein are sufficient to allow mammalian adaption of avian influenza viruses. They lead to enhanced virus propagation in mammalian cells and increased plaque size, suggesting shorter replication cycles. On a molecular level, I show the importance of these specific residues for strongly enhanced mRNA production as well as viral protein production in mammalian cells. At the same time this adaptive changes are not disadvantageous in avian cells. My study suggests that the D74N and/or P3S+R41K+D74N substitutions are involved in the temperature adaptation of the polymerase of avian influenza virus from birds to mammals. They also confer the ability to the otherwise strictly avian influenza virus to replicate in mice and cause disease. Global gene expression of mammalian A549 cells upon infection with FPV harboring NS-MA (FPV-NSMA) or with FPV harboring NS-MA mutants (FPV-NSMA_D74N and FPV-NSMA_ P3S+R41K+D74N) viruses are qualitatively similar in the activation of biological host inflammatory response including type I interferon (IFN) and chemokine signaling, However, in comparison to FPV-NSMA virus infected cells, the mutants NS1-MAD74N and/or NS1-MAP3S+R41K+D74N elicit a quantitatively weaker host inflammatory response of type I interferon (IFN) and pro-inflammatory cytokine/chemokine response. This points to a reduced innate immune response, which is correlated with increased viral replication competence. Together, these adaptive mutations in the NS1 protein seem to allow to establish successful infections in mammalian cells.

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