NS reassortment of an H7-type highly pathogenic avian influenza virus affects its propagation by1 altering the regulation of viral RNA production and anti-viral host response

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WangZhongfang_2010_09_24.pdf (1.95 MB)

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2010

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DOI:
http://dx.doi.org/10.22029/jlupub-13599

Abstract

Since 1997 the emergence of H5-type highly pathogenic avian influenza virus (HPAIV) hasresulted in major losses to the poultry industry and caused over 500 human infections withapproximately 60% mortality. In Europe H7-type HPAIV have been circulating for a longtime with very little pathogenicity for humans. Nevertheless, the ability of influenza viruses(IV) to mix their segmented genomes upon double infections could lead to the emergence ofnew, reassortant H7-type HPAIV with altered characteristics that could pose an additionalthreat to humans. The viral NS segments encoding the NS1 and NS2/NEP proteins can affectthe anti-viral host responses, inhibit cellular mRNA processing and enhance viral mRNAtranslation. NS1 contributes to high virulence and host range variation and it was reported thatNS segments of H5-type HPAIV isolated after 1998 can enhance replication of human IVreassortants in mammalian cells. Still it is not clear how the NS allele type, the subtype andthe year of isolation of the parental virus affects host range, genome replication/transcription,viral propagation and pathogenicity of an H7-type reassortant.In order to elucidate several of these important questions reassortant A/FPV/Rostock/34(H7N1) HAPIV with NS segments from H5- and H7-type avian IV strains were generated byreverse genetics. Virological characterizations demonstrated that growth kinetics of thereassortant viruses differed from the wild type FPV and depended on the mammalian or avianorigin of the infected cells. Surprisingly, the different reassortant NS segments were not onlyresponsible for alterations in the anti-viral host response, but furthermore affected viralgenome replication/transcription and its intra-cellular transport. Further experimentsdemonstrated that the effects on accumulation of viral RNA species depended on the specificNS-segment as well as on the genetic background of the viral polymerase. IFN-betaexpression and apoptosis induction were found to be inversely correlated to viral growth,while the NS allele, virus subtype and NS1 protein expression levels showed no correlation.Even though it is likely that the multiple effects of the NS1 protein act on many viral and hostprocesses as why one can not conclude which of the effects is the most important for the viralreplication ability, these results demonstrate that the origin of NS segment can affect thereplication efficiency, host range and pathogenicity of H7-type HPAIV.

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