IRF-3-dependent and augmented target genes during viral infection

Andersen, Jardar; VanScoy, Sarah; Tf, Cheng; Pereira, Dolores; Nc, Reich

doi:10.1038/sj.gene.6364449

Cited by 103 publications

(108 citation statements)

References 54 publications

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“…It remains to be seen which of these functions, if either, is required for apoptosis inhibition by CSFV. Active IRF3 induces expression of a number of pro-apoptotic genes (Andersen et al, 2007), and this may be inhibited in CSFV-infected cells. The observation that apoptosis can be induced in SK6 cells, reported to have a defective interferon response (Ruggli et al, 2003), implies that the two pathways may be independent in these cells.…”

Section: Discussionmentioning

confidence: 99%

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

Johns

Bensaude

Rocca

et al. 2009

Journal of General Virology

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Classical swine fever virus (CSFV) causes severe disease in pigs associated with leukopenia, haemorrhage and fever. We show that CSFV infection protects endothelial cells from apoptosis induced by the dsRNA mimic, pIpC, but not from other apoptotic stimuli, FasL or staurosporine. CSFV infection inhibits pIpC-induced caspase activation, mitochondrial membrane potential loss and cytochrome c release as well as the pro-apoptotic effects of truncated Bid (tBid) overexpression. The CSFV proteins N pro and E rns both contribute to CSFV inhibition of apoptosis. We conclude that CSFV infection can inhibit apoptotic signalling at multiple levels, including at the caspase-8 and the mitochondrial checkpoints. By supporting viral replication, endothelial cells may promote CSFV pathogenesis. INTRODUCTIONClassical swine fever virus (CSFV), a pestivirus within the family Flaviviridae, is related in terms of its sequence and genome organization to other members of the flavivirus group that give rise to human diseases such as hepatitis C and dengue fever. CSFV is a positive-sense RNA virus, and is the causative agent of classical swine fever (CSF), a notifiable disease of pigs (Le Potier et al., 2006). Disease outbreaks are associated with considerable economic loss and adverse effects on animal welfare (Paton & GreiserWilke, 2003). In its most virulent form, CSFV infection causes severe immunopathological signs, including leukopenia, haemorrhage and fever, accompanied by high morbidity and mortality. However, within an infected population, some animals are found to recover or develop chronic disease (Le Potier et al., 2006). These observations suggest a complex interplay between the virus and the host immune system. CSFV infection is accompanied by depression of cellular immune defences (Ganges et al., 2008) and particularly innate responses mediated by interferon (Bensaude et al., 2004; La Rocca et al., 2005; Ruggli et al., 2005;Seago et al., 2007). In vivo, elevated levels of cell death by apoptosis are thought to account for the characteristic depletion of circulating leukocytes (Sanchez-Cordon et al., 2002;Summerfield et al., 2000Summerfield et al., , 2001. However, it has been found that apoptotic cells rarely contain detectable viral antigen, indicating that apoptotic cells are generally not CSFV-infected (Choi et al., 2004;Sato et al., 2000;Summerfield et al., 2001). This finding, together with the observation that acutely infected animals develop high viral loads, suggest a possible role for cell populations that are resistant to virus-induced apoptosis. These may include endothelial cells.Apoptosis is a controlled cell death programme employed by multicellular organisms to eliminate damaged, aberrant or infected cells (Benedict et al., 2002). A characteristic of apoptotic cell death is the activation of the caspase family of proteases. Caspases that function near the apex of cell death cascades are designated initiators and include caspases-8 and -9, whereas those involved in the terminal stages of cell death, such as ...

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Section: Discussionmentioning

confidence: 99%

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

Johns

Bensaude

Rocca

et al. 2009

Journal of General Virology

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“…CRISPR-Cas9 knockout of either cytosolic cGAS or STING reduced activation of downstream IRF3 target genes ISG54, ISG56 and the NF-κB target CCL5 post-IR (Fig 3a and Extended data 3a) 17, 18 . Attenuated STAT1 activation and IFITM1 induction was also evident in cGAS-STING knockouts (Fig 3b and Extended data 3c).…”

mentioning

confidence: 93%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,175

780

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Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumor microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumor responses to radiotherapy1. An enigmatic feature of this phenomenon is its delayed onset (days), in contrast to the acute DNA damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate limiting steps that are essential for DNA-damage induced inflammation. Here, we show that cell cycle progression through mitosis following DNA double-strand breaks (DSBs) leads to the formation of micronuclei, which precede activation of inflammatory signaling and are a repository for the pattern recognition receptor cGAS. Inhibiting progression through mitosis or loss of pattern recognition by cGAS-STING impaired interferon signaling. Moreover, STING loss prevented the regression of abscopal tumors in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

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“…IFN␤ was also added to both conditions to eliminate any non-canonical signaling induced by IFN␤-mediated, STAT1-independent signaling. Not surprisingly, gene array analysis of IRF7-and IKK⑀-expressing cells demonstrated the induction of previously characterized IRF3-regulated genes, namely the members of the IFN-inducible p56 family (IFNinduced protein with tetratricopeptide repeats 1 IFIT1/ISG56, IFIT2/ISG54, and IFIT3/ISG60) (39 -41), and radical S-adenosyl methionine domain containing 2 (RSAD2) (41). However, in addition to this subset, IRF7 activation resulted in cytokine induction (including IFN-I, as previously described (25,26,31,52), as well as a large subset of genes previously thought to be dependent on IFN-I signaling (Fig.…”

Section: Defining the Irf7 Transcriptome In The Absence Of Ifn-i And mentioning

confidence: 99%

“…To address this question, we aimed to identify an ISRE that could be bound by both ISGF3 and IRF7 with relative equal affinities. For these purposes, we focused on the manipulation of a well-characterized ISRE motif from the IFN-stimulated gene 15 (ISG15) (40,41,53). To this end, IRF7 or the components of ISGF3 (STAT1, STAT2, IRF9) were exogenously produced in fibroblasts and activated with either IKK⑀ or IFN␤ ( Fig.…”

Section: Profiling Virus-induced Genes In the Absence Of Ifn-i And -Imentioning

confidence: 99%

Transcription Factor Redundancy Ensures Induction of the Antiviral State

Schmid

Mordstein

Kochs

et al. 2010

Journal of Biological Chemistry

112

101

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The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFNlike transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN-stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRFspecific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggest that IRF7 can induce an IFNlike transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state.

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IRF-3-dependent and augmented target genes during viral infection

Cited by 103 publications

References 54 publications

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

Classical swine fever virus infection protects aortic endothelial cells from pIpC-mediated apoptosis

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Transcription Factor Redundancy Ensures Induction of the Antiviral State

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