Active NF-κB signalling is a prerequisite for influenza virus infection

Nimmerjahn, Falk; Dudziak, Diana; Dirmeier, Ulrike; Hobom, Gerd; Riedel, Alexander; Schlee, Martin; Staudt, Louis M.; Rosenwald, Andreas; Behrends, Uta; Bornkamm, Georg W.; Mautner, Josef

doi:10.1099/vir.0.79958-0

Cited by 194 publications

(162 citation statements)

References 39 publications

(37 reference statements)

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“…We and others could show that influenza A virus infection is associated with expression of NF-Bdependent gene products such as proinflammatory cytokines in cell culture (6, 53, 56 -58) and in vivo models (59 -61). Work from our group and others revealed that influenza A virus replication induces and depends on activation of NF-B (31,42,62,63), most presumably by subsequent activation of caspases that enhance the passive release of viral ribonucleoproteins from the nucleus in late phases of viral replication. During preparation of this manuscript, Kumar et al (64) additionally claimed that NF-B signaling is important for the synthesis of viral RNA in influenza virus-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

Schmolke¹,

Viemann²,

Roth³

et al. 2009

The Journal of Immunology

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Systemic infections of humans and birds with highly pathogenic avian influenza A viruses of the H5N1 subtype are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm. Growing evidence supports the role of endothelial cells in these processes. The aim of this study was to elucidate determinants of this strong response in endothelial cells with a focus on the transcription factor NF-κB. This factor is known as a major regulator of inflammatory response; however, its role in influenza virus replication and virus-induced immune responses is controversially discussed. By global mRNA profiling of infected cells in the presence or absence of a dominant negative mutant of IκB kinase 2 that specifically blocks the pathway, we could show that almost all H5N1 virus-induced genes depend on functional NF-κB signaling. In particular, activation of NF-κB is a bottleneck for the expression of IFN-β and thus influences the expression of IFN-dependent genes indirectly in the primary innate immune response against H5N1 influenza virus. Control experiments with a low pathogenic influenza strain revealed a much weaker and less NF-κB-dependent host cell response.

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Section: Discussionmentioning

confidence: 99%

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

Schmolke¹,

Viemann²,

Roth³

et al. 2009

The Journal of Immunology

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“…The susceptibility of cells to influenza A virus is known to depend on the level of NF-B activation (22,23). Normally, IB␣ silences NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, active NF-B signaling has been demonstrated to be a prerequisite for efficient influenza A virus infection of human cells (22,23). The inhibitory subunit, IB␣, maintains NF-B in an inactive state and is degraded in the course of NF-B activation.…”

Section: Simultaneous Application Of Par 2 -Cap and Ifn-␥ Reduces Ib␣mentioning

confidence: 99%

Agonists of Proteinase-Activated Receptor-2 Enhance IFN-γ-Inducible Effects on Human Monocytes: Role in Influenza A Infection

Feld¹,

Shpacovitch²,

Ehrhardt³

et al. 2008

The Journal of Immunology

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Proteinase-activated receptor-2 (PAR2) is expressed by different types of human leukocytes and involved in the development of inflammatory and infectious diseases. However, its precise role in the regulation of human monocyte and macrophage function during viral infection remains unclear. Also, the ability of PAR2 agonists to enhance the effects induced by immune mediators during infection or inflammation is still poorly investigated. Therefore, we investigated the ability of a PAR2 agonist to enhance IFN-γ-induced suppression of influenza A virus replication in human monocytes. We found that this effect correlates with an increased abundance of IκBα after costimulation of cells with PAR2 agonist and IFN-γ. Remarkably, coapplication of PAR2 agonist and IFN-γ also enhances the effects of IFN-γ on IFN-γ-inducible protein 10 kDa release, and CD64 and αVβ3 surface expression by human monocytes. Together, these findings indicate a potentially protective role of PAR2 activation during the progression of influenza A virus infection. This effect could be associated with the ability of PAR2 agonists to enhance IFN-γ-induced protective effects on human monocytes.

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“…They have multiple signal effects, one of them being activation of the transcription factor NF-kappaB (54Á56). But NF-kappaB has been reported to stimulate replication of the influenza virus and to be necessary for its replication (57,58). More replication of the influenza virus (causing enhanced viral load) must in turn be expected to lead to enhanced stimulation of the expression and secretion of various cytokines, including TNF-a.…”

Section: Evolution Of Virulence Properties In Influenza Virusesmentioning

confidence: 99%

Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?

Christophersen¹,

Haug

2006

Microbial Ecology in Health and Disease

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The world is now extremely poorly prepared to counter a possible pandemic of hypervirulent H5N1 influenza. Most countries are planning for nothing worse than the Spanish flu pandemic. It may be possible that this can in large measure be explained as a consequence of an epidemic of wishful thinking, which may already have infected the health authorities (and parts of the scientific community as well) in most countries in the world. However, it may also be possible that it can have happened as a consequence of too little contact between medical scientists and more general biologists (natural scientists) from disciplines such as ornithology, ecology and evolutionary biology. This may have led to a lack of proper understanding among medical scientists (and health bureaucrats) of the nature of evolutionary processes affecting influenza viruses, as regards the evolution of host species adaptation, infectivity and virulence properties, and also a lack of appreciation of the ways in which such forms of evolutionary adaptation depend on ecological boundary conditions that have radically changed, comparing the world in 2006 to the world in 1918. While the Spanish flu virus possibly might be compared to a one-headed monster, it may be possible that highly virulent varieties of H5N1 virus might better be compared to a three-headed one Á because there is evidence of at least three independent virulence factors connected with three different genes. It is highly unlikely that all of the high-virulence alleles will simultaneously mutate and disappear if and when the haemagglutinin gene changes so as to make the haemagglutinin molecule better adapted for the human-type (alpha-2,6-linked) receptor (which is a necessary prerequisite in order that a pandemic with H5N1 virus may start). It is more probable that evolutionary adaptation of the haemagglutinin of H5N1 viruses to the human-type receptor will happen without any simultaneous change in those other genetic properties that now are important for explaining the exceptionally high virulence of certain strains of avian-adapted H5N1 influenza virus. The change of the haemagglutinin molecule from avian adaptation to human adaptation must be expected to act as an additional virulence factor because it will enhance the total number of cells that can be infected (per host organism), increase the total rate of virus replication and potentiate the effects of the other virulence factors already present. The monster will then have four heads, not three, and case fatality rates must be expected to become even higher than they have been until now, perhaps reaching as high as 98 Á99% (at least in poor countries with less than optimal nutrition).

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Active NF-κB signalling is a prerequisite for influenza virus infection

Cited by 194 publications

References 39 publications

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

Agonists of Proteinase-Activated Receptor-2 Enhance IFN-γ-Inducible Effects on Human Monocytes: Role in Influenza A Infection

Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?

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