Influenza virus activation of the interferon system

Killip, Marian J.; Fodor, Ervin; Randall, R. E.

doi:10.1016/j.virusres.2015.02.003

Cited by 174 publications

(155 citation statements)

References 182 publications

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“…The NS1 protein limits IFN expression by targeting multiple components of the IFN induction cascade (Killip et al, 2015).…”

Section: Ns1 Is Required To Prevent Nf-k B and Irf3 Activation In Celmentioning

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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“…The NS1 protein limits IFN expression by targeting multiple components of the IFN induction cascade (Killip et al, 2015).…”

Section: Ns1 Is Required To Prevent Nf-k B and Irf3 Activation In Celmentioning

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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“…Therefore, type I IFNs play an important role in the host defense system against viruses, including IAV (12)(13)(14). Influenza viral RNAs with a 5=ppp trigger the retinoic acid-inducible gene 1 (RIG-I)-mediated signaling pathway (15). RIG-I recruits mitochondrial antiviral signaling protein (MAVS), which activates downstream kinases IB kinaseε (IKKε) and TBK1 (16).…”

mentioning

confidence: 99%

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Xia

Vijayan

Pritzl

et al. 2016

J Virol

114

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Influenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity. IMPORTANCE Influenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN Influenza virus infection causes seasonal and pandemic influenza with significant morbidity and mortality in humans (1). Outbreaks of avian influenza by highly pathogenic H5N1 and H7N9 viruses have raised the risk for the occurrence of another influenza pandemic (2-4). The genome of influenza A virus (IAV) encodes at least 11 proteins, including hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix proteins (M1 and M2), nonstructural proteins (NS1 and NS2), polymerase proteins (PA, PB1, and PB2), and PB1-F2 (5, 6). Antiviral drugs against influenza that block the function of viral proteins such as NA and M2 were developed to treat the infection. However, because of the high mutability, several strains of seasonal influenza and avian influenza viruses were shown to be resistant to the current antiviral drugs (6-8). Therefore, designing new therapeutics and identifying cellular targets of the infection are important to effectively control influenza.Type I interferons (IFNs), which include multiple IFN-␣ subtypes and IFN-␤, induce the expression of numerous interferonstimulated genes (ISGs) that establish antiviral states (9-11). Therefore, type I IFNs play an important role in the host defense system against viruses, including IAV (12)(13)(14). Influenza v...

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“…Interferons have been implicated to cause increased disease severity during influenza infections [28] while suppressing viral replication. It is also important to note that the most commonly implicated IFNs are the type I (IFN α and IFN β) and type III IFN (IFN λ) in influenza infection [29].…”

Section: Discussionmentioning

confidence: 99%

The Correlation of IFN <i>γ</i> to the Preferential Isolation of Influenza Type B over Type A Viruses in Madin Darby Canine Kidney Cells

Byaruhanga¹,

Bagaya²,

Namulondo³

et al. 2017

OJMM

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The isolation of influenza viruses in Madin Darby Canine Kidney (MDCK) cells has shown preferential isolation of a great percentage of Influenza B strains at the first passage than Influenza A strains. During in vitro isolation of Influenza viruses, majority of type A viruses are not confirmed as positive isolates by Hemagglutination (HA) assay despite having higher virulence and pathogenicity versus influenza B viruses. This study investigated the differences in IFN-γ and IL-10 cytokines secreted by MDCK cells upon exposure to the viruses and thus provided possible answers as to why influenza type B can easily be isolated from MDCK cells compared to influenza A. Positive influenza viruses were inoculated onto MDCK cells. IFN-γ and IL-10 cytokines stimulated by the viruses in MDCK cells were measured by indirect ELISA at 1 hour, 12 hours, 48 hours and 72 hours post inoculation (pi). A total of 46 specimens, with 23 specimens from each virus type were analyzed. IFN-γ was significantly higher at 1 hour pi in MDCK cells for influenza type A at p value of 0.024 than type B. No statistical significance was observed in means of cytokine IL-10 between influenza type A and type B. The study may show that IFN-γ is correlated to the preferential isolation of influenza type B over type A viruses. Anti-inflammatory cytokines may not necessarily be playing a role in the preferential growth of influenza type B, a less virulent type over influenza type A in MDCK cells.

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Influenza virus activation of the interferon system

Abstract: HighlightsWe summarise the literature regarding activation of the IFN response by influenza viruses.We consider evidence concerning the identity of the viral RNA responsible for IFN induction.The link between IFN induction and defective virus genomes is discussed.

Cited by 174 publications

References 182 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

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

The Correlation of IFN <i>γ</i> to the Preferential Isolation of Influenza Type B over Type A Viruses in Madin Darby Canine Kidney Cells

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Influenza virus activation of the interferon system

Abstract: HighlightsWe summarise the literature regarding activation of the IFN response by influenza viruses.We consider evidence concerning the identity of the viral RNA responsible for IFN induction.The link between IFN induction and defective virus genomes is discussed.

Cited by 174 publications

References 182 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

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

The Correlation of IFN &lt;i&gt;γ&lt;/i&gt; to the Preferential Isolation of Influenza Type B over Type A Viruses in Madin Darby Canine Kidney Cells

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The Correlation of IFN <i>γ</i> to the Preferential Isolation of Influenza Type B over Type A Viruses in Madin Darby Canine Kidney Cells