Inability of NS1 protein from an H5N1 influenza virus to activate PI3K/Akt signaling pathway correlates to the enhanced virus replication upon PI3K inhibition

Li, Weizhong; Wang, Gefei; Zhang, Heng; Shen, Yan‐Qin; Jian-Ping, Dai; Wu, Liqi; Zhou, Jianrong; Jiang, Zhiwu; Li, Kangsheng

doi:10.1186/1297-9716-43-36

Cited by 19 publications

(16 citation statements)

References 36 publications

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“…Therefore, we speculate that, through a currently unknown mechanism, the interaction of NS1-ESEV (but not NS1-ESKV) with Dlg-1 stimulates the PI3K/Akt pathway, resulting in efficient virus replication. While this study was under way, Li et al (64) described an H5N1 influenza virus that no longer activated the PI3K/Akt pathway. The NS1 protein of this virus possesses the NS1-ESKV motif, consistent with our finding that NS1-ESKV affects PI3K/Akt activation.…”

Section: Discussionmentioning

confidence: 94%

Synergistic Effect of the PDZ and p85β-Binding Domains of the NS1 Protein on Virulence of an Avian H5N1 Influenza A Virus

Fan

Macken

Liu

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 94%

Synergistic Effect of the PDZ and p85β-Binding Domains of the NS1 Protein on Virulence of an Avian H5N1 Influenza A Virus

Fan

Macken

Liu

et al. 2013

J Virol

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“…A PI3K inhibitor decreased expression of CD16 on microglial cells (central nervous system-resident macrophages), suggesting a link between PI3K signalling and Fc receptor expression [69]. Although seasonal H1N1 and H3N2 IAV activate the PI3K signalling pathway in mouse AMs, an H5N1 IAV fails to do the same in infected epithelial cells [70,71]. While the status of PI3K signalling in H5-infected macrophages has not been investigated, perhaps a failure to activate the PI3K pathway in macrophages is one explanation for the observed decrease in CD16/32 expression that leads to the decreased phagocytic capacity of H5-infected macrophages.…”

Section: Iav Replication and Macrophage Phagocytosismentioning

confidence: 99%

Influenza virus replication in macrophages: balancing protection and pathogenesis

Cline

Beck

Bianchini

2017

Journal of General Virology

103

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Macrophages are essential for protection against influenza A virus infection, but are also implicated in the morbidity and mortality associated with severe influenza disease, particularly during infection with highly pathogenic avian influenza (HPAI) H5N1 virus. While influenza virus infection of macrophages was once thought to be abortive, it is now clear that certain virus strains can replicate productively in macrophages. This may have important consequences for the antiviral functions of macrophages, the course of disease and the outcome of infection for the host. In this article, we review findings related to influenza virus replication in macrophages and the impact of productive replication on macrophage antiviral functions. A clear understanding of the interactions between influenza viruses and macrophages may lead to new antiviral therapies to relieve the burden of severe disease associated with influenza viruses.

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“…The products of the NS segment have indeed been implicated in host adaptation and pathogenicity. For instance, Li et al concluded that the NS1 gene contributed to the virulence of H5N1 avian influenza viruses ( 16 ), while adaptive mutations in both the NS1 protein and NEP were found when A/Hong Kong/1968 (H3N2) was adapted to increased virulence in mice ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity

Turnbull

Wise

Nicol

et al. 2016

J Virol

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Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts. To test this, a number of clade A and B avian virus-derived NS segments were introduced into human H1N1 and H3N2 viruses. In no case was the peak virus titer substantially reduced following infection of various mammalian cell types. Exemplar reassortant viruses also replicated to similar titers in mice, although mice infected with viruses with the avian virus-derived segment 8s had reduced weight loss compared to that achieved in mice infected with the A/Puerto Rico/8/1934 (H1N1) parent. In vitro, the viruses coped similarly with type I interferons. Temporal proteomics analysis of cellular responses to infection showed that the avian virus-derived NS segments provoked lower levels of expression of interferon-stimulated genes in cells than wild type-derived NS segments. Thus, neither the A nor the B allele of avian virus-derived NS segments necessarily attenuates virus replication in a mammalian host, although the alleles can attenuate disease. Phylogenetic analyses identified 32 independent incursions of an avian virus-derived A allele into mammals, whereas 6 introductions of a B allele were identified. However, A-allele isolates from birds outnumbered B-allele isolates, and the relative rates of Aves-to-Mammalia transmission were not significantly different. We conclude that while the introduction of an avian virus segment 8 into mammals is a relatively rare event, the dogma of the B allele being especially restricted is misleading, with implications in the assessment of the pandemic potential of avian influenza viruses. IMPORTANCE Influenza A virus (IAV) can adapt to poultry and mammalian species, inflicting a great socioeconomic burden on farming and health care sectors. Host adaptation likely involves multiple viral factors. Here, we investigated the role of IAV segment 8. Segment 8 has evolved into two distinct clades: the A and B alleles. The B-allele genes have previously been suggested to be restricted to avian virus species. We introduced a selection of avian virus A- and B-allele segment 8s into human H1N1 and H3N2 virus backgrounds and found that these reassortant viruses were fully competent in mammalian host systems. We also analyzed the currently available public data on the segment 8 gene distribution and found surprisingly little evidence for specific avian host restriction of the B-clade segment. We conclude that B-allele segment 8 genes are, in fact, capable of supporting infection in mammals and that they should be considered during the assessment of the pandemic risk of zoonotic influenza A viruses.

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Inability of NS1 protein from an H5N1 influenza virus to activate PI3K/Akt signaling pathway correlates to the enhanced virus replication upon PI3K inhibition

Cited by 19 publications

References 36 publications

Synergistic Effect of the PDZ and p85β-Binding Domains of the NS1 Protein on Virulence of an Avian H5N1 Influenza A Virus

Synergistic Effect of the PDZ and p85β-Binding Domains of the NS1 Protein on Virulence of an Avian H5N1 Influenza A Virus

Influenza virus replication in macrophages: balancing protection and pathogenesis

Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity

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