Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein

Fernández-Sesma, Ana; Marukian, Svetlana; Ebersole, Barbara J.; Kaminski, Denise A.; Park, Man Seong; Yuen, Tony; Sealfon, Stuart C.; Garcı́a-Sastre, Adolfo; Moran, Thomas M.

doi:10.1128/jvi.02381-05

Cited by 265 publications

(300 citation statements)

References 50 publications

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“…In 2007, Pauli et al (2008) reported that IAVs suppress type I IFN signalling by upregulating the suppressor of cytokine signalling-3 (SOCS-3) protein, which is a potent endogenous inhibitor of JAK/STAT signalling (Pauli et al, 2008). In addition to inhibiting innate immunity by preventing type I IFN release, IAVs attenuate adaptive immunity by inhibiting the maturation of human dendritic cells and the capacity of dendritic cells to activate T-cell responses (Fernandez-Sesma et al, 2006). In addition to the blockade of innate and adaptive immunity, Krug et al (2003) found that the NS1 proteins from A/Tx/36/91 suppressed host gene expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of the IFN-β response in H3N2 canine influenza virus infection

San

et al. 2016

Journal of General Virology

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Canine influenza viruses (CIVs) circulate continuously in the dog population, providing opportunities for exposure to humans and other species. Although the dog genome has been sequenced, innate immunity in dogs is not well characterized, which limits the understanding of H3N2 canine influenza virus pathogenesis. Equally, how this virus evades the canine host innate immune response to successfully establish infection remains unclear. To analyse the IFN-b response to CIV infection in Madin-Darby canine kidney cells, the canine IFN-b promoter sequence and its positive regulatory domain motifs were first cloned and identified using a luciferase reporter system. Next, we found that infection with the CIV strain GD/12 blocked the IFN-b response primarily by inhibiting the NF-k B and IFN regulatory factor 3 (IRF3) signalling pathways. Expression of GD/12 non-structural protein 1 alone was sufficient to inhibit Sendai virus-induced NF-k B and IRF3 activation by suppressing p65 and IRF3 phosphorylation, suggesting the important role of this protein in the CIV-mediated inhibition of the IFN-b response. These results suggest that inhibition of the IFN-b signalling pathway may have played a role in CIV establishment and spread in dog populations.

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Section: Discussionmentioning

confidence: 99%

Identification of the IFN-β response in H3N2 canine influenza virus infection

San

et al. 2016

Journal of General Virology

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“…Recently, NS1 has been shown to limit the induction of numerous specific transcriptional events associated with the maturation of human dendritic cells (DCs) in response to virus infection (38). In particular, expression of IL-12 p35 (a subunit of the proinflammatory and immunoregulatory cytokine IL-12) was found to be inhibited in DCs infected with recombinant viruses expressing NS1 (38).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, expression of IL-12 p35 (a subunit of the proinflammatory and immunoregulatory cytokine IL-12) was found to be inhibited in DCs infected with recombinant viruses expressing NS1 (38). IL-12 is a key regulator of host innate and adaptive immune responses during infection: it enhances the cytolytic activity of natural killer (NK) cells and CD8 ϩ T cells, and contributes to the optimal production of IFN-␥ (39).…”

Section: Discussionmentioning

confidence: 99%

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

Hale

Jackson

Chen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

331

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Influenza A virus NS1 is a multifunctional protein, and in virusinfected cells NS1 modulates a number of host-cell processes by interacting with cellular factors. Here, we report that NS1 binds directly to p85␤, a regulatory subunit of phosphatidylinositol-3-kinase (PI3K), but not to the related p85␣ subunit. Activation of PI3K in influenza virus-infected cells depended on genome replication, and showed kinetics that correlated with NS1 expression. Additionally, it was found that expression of NS1 alone was sufficient to constitutively activate PI3K, causing the phosphorylation of a downstream mediator of PI3K signal transduction, Akt. Mutational analysis of a potential SH2-binding motif within NS1 indicated that the highly conserved tyrosine at residue 89 is important for both the interaction with p85␤, and the activation of PI3K. A mutant influenza virus (A͞Udorn͞72) expressing NS1 with the Y89F amino acid substitution exhibited a small-plaque phenotype, and grew more slowly in tissue culture than WT virus. These data suggest that activation of PI3K signaling in influenza A virus-infected cells is important for efficient virus replication.Akt phosphorylation ͉ multifunctional NS1 protein ͉ reverse genetics

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“…The NS1 protein of influenza virus and the V protein of SeV inhibit the induction of type I IFNs by blocking intracellular dsRNA signaling (20,(31)(32)(33)(34). The influenza virus NS1 protein has also been shown to inhibit viral induction of DC maturation (5,35). Thus, we hypothesized that SeV-C may encode an impaired type I IFN antagonist allowing stronger DC stimulation by viral dsRNA than SeV-52.…”

Section: Strong DC Maturation By Sev-c Is Not Antagonized By a Sev Wimentioning

confidence: 99%

A Novel Role for Viral-Defective Interfering Particles in Enhancing Dendritic Cell Maturation

Yount

Kraus

Horvath

et al. 2006

The Journal of Immunology

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108

152

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Dendritic cell (DC) maturation is a crucial event in the development of adaptive immune responses that confer long-lasting protection against reinfection with the same virus. Sendai virus strain Cantell has a particularly strong ability to mature DCs independently of type I IFNs and TLR signaling, currently the best-described pathways for the induction of DC maturation. In this study, we demonstrate that defective-interfering (DI) particles present in Sendai virus-Cantell stocks are required for its robust DC maturation ability. DI particles contain incomplete genomes that are unable to replicate unless the viral polymerase is supplied by coinfection with complete virus. Accordingly, the improvement in the virus-induced maturation of DCs provided by DI particles requires standard virus coinfection and likely results from increased production of dsRNA replication intermediaries. This unique ability of DI particles to stimulate DC maturation cannot be mimicked by simply increasing the dose of standard virus. Furthermore, viruses with weak DC maturation abilities can be converted into potent DC stimulators with the addition of DI particles, supporting a potential application for DI particles as a novel natural adjuvant for viral immunizations.

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Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein

Abstract: Both antibodies and T cells contribute to immunity against influenza virus infection. However

Cited by 265 publications

References 50 publications

Identification of the IFN-β response in H3N2 canine influenza virus infection

Identification of the IFN-β response in H3N2 canine influenza virus infection

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

A Novel Role for Viral-Defective Interfering Particles in Enhancing Dendritic Cell Maturation

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