The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB

Dam, Sharmistha; Pleschka, Stephan; Schmitz, M. Lienhard

doi:10.1128/jvi.00946-16

Cited by 16 publications

(16 citation statements)

References 61 publications

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“…We do not know whether the amplification resulted in the acquisition of additional adaptations. Titers of the virus stocks were determined by titration in MDCK II cells performed in triplicates, as described previously (69).…”

Section: Methodsmentioning

confidence: 99%

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Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks

Weber

Dam

Saul

et al. 2019

J Virol

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Influenza A viruses (IAVs) quickly adapt to new environments and are well known to cross species barriers. To reveal a molecular basis for these phenomena, we compared the Ser/Thr and Tyr phosphoproteomes of murine lung epithelial cells early and late after infection with mouse-adapted SC35M virus or its nonadapted SC35 counterpart. With this analysis we identified a large set of upregulated Ser/Thr phosphorylations common to both viral genotypes, while Tyr phosphorylations showed little overlap. Most of the proteins undergoing massive changes of phosphorylation in response to both viruses regulate chromatin structure, RNA metabolism, and cell adhesion, including a focal adhesion kinase (FAK)-regulated network mediating the regulation of actin dynamics. IAV also affected phosphorylation of activation loops of 37 protein kinases, including FAK and several phosphatases, many of which were not previously implicated in influenza virus infection. Inhibition of FAK proved its contribution to IAV infection. Novel phosphorylation sites were found on IAV-encoded proteins, and the functional analysis of selected phosphorylation sites showed that they either support (NA Ser178) or inhibit (PB1 Thr223) virus propagation. Together, these data allow novel insights into IAV-triggered regulatory phosphorylation circuits and signaling networks. IMPORTANCE Infection with IAVs leads to the induction of complex signaling cascades, which apparently serve two opposing functions. On the one hand, the virus highjacks cellular signaling cascades in order to support its propagation; on the other hand, the host cell triggers antiviral signaling networks. Here we focused on IAV-triggered phosphorylation events in a systematic fashion by deep sequencing of the phosphoproteomes. This study revealed a plethora of newly phosphorylated proteins. We also identified 37 protein kinases and a range of phosphatases that are activated or inactivated following IAV infection. Moreover, we identified new phosphorylation sites on IAV-encoded proteins. Some of these phosphorylations support the enzymatic function of viral components, while other phosphorylations are inhibitory, as exemplified by PB1 Thr223 modification. Our global characterization of IAV-triggered patterns of phospho-proteins provides a rich resource to further understand host responses to infection at the level of phosphorylation-dependent signaling networks.

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Section: Methodsmentioning

confidence: 99%

“…Generation of recombinant SC35 and SC35M viruses. The pHW2000 plasmids containing the cloned segments of SC35 and SC35M (12) were transfected into a coculture of 293T/MDCK II cells (ratio 3:1) using Lipofectamine 2000 and further handled as described previously (69).…”

Section: Methodsmentioning

confidence: 99%

Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks

Weber

Dam

Saul

et al. 2019

J Virol

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“…Although these clinical developments are promising, there are still open questions, mainly with regard to the mechanism of action-that is, the balance between virus-supportive NF-κB functions in the course of the virus life cycle and its antiviral activities by inducing robust inflammatory and antiviral responses. A recent study using genetic mouse knockouts of NF-κB transcription factors led to some controversial data about the consequences of complete versus partial inhibition of NF-κB functions for IV replication (Dam et al 2016). In addition, this study emphasized the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB.…”

Section: Nuclear Factor κBmentioning

confidence: 96%

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

Ludwig

Hrincius

Boergeling

2019

Cold Spring Harb Perspect Med

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Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strategies of antiviral intervention. Here, we will summarize the current knowledge of activation and function of influenza virus-induced signaling pathways with a focus on nuclear factor (NF)-κB signaling, mitogen-activated protein kinase cascades, and the phosphatidylinositol-3-kinase pathway. We will discuss the opportunities and drawbacks of targeting these signaling pathways for antiviral intervention.

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“…Upon activation, NF-κB translocates into the nucleus to induce expression of tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β with multiple downstream effects, including inflammasome activation, apoptosis, and, importantly, further stimulation of NF-κB activation, which creates an inflammatory positive feedback loop. Despite clear evidence that NF-κB plays an important protective role in the immune response to influenza infection 116 and that impaired production of downstream cytokines, such as IL-6, can increase influenza-related mortality, 117 other studies have shown NF-κB can be “hijacked” to promote influenza replication, 118 , 119 resulting in some debate over its overall role in disease progression. 119 Inhibition of NF-κB has been suggested to be a possible treatment strategy for influenza infection.…”

Section: Molecular Mechanisms and Cellular Biologymentioning

confidence: 99%

“…Despite clear evidence that NF-κB plays an important protective role in the immune response to influenza infection 116 and that impaired production of downstream cytokines, such as IL-6, can increase influenza-related mortality, 117 other studies have shown NF-κB can be “hijacked” to promote influenza replication, 118 , 119 resulting in some debate over its overall role in disease progression. 119 Inhibition of NF-κB has been suggested to be a possible treatment strategy for influenza infection. 120 , 121 Although the role of NF-κB in SARS-CoV-2 has yet to be fully elucidated, the high levels of TNF-α and IL-6 in patients with severe COVID-19 infection are strongly suggestive of its activation.…”

Section: Molecular Mechanisms and Cellular Biologymentioning

confidence: 99%

Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

Stubbs

Koutnik

Goldberg

et al. 2020

Med

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The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB

Abstract: The role of NF-B in influenza A virus (IAV) infection does not

Cited by 16 publications

References 61 publications

Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks

Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

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