Bluetongue virus infection: Activation of the MAP kinase-dependent pathway is required for apoptosis

Mórtola, Eduardo; Larsen, Alejandra Edith

doi:10.1016/j.rvsc.2010.04.001

Cited by 10 publications

(10 citation statements)

References 28 publications

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“…Although we have not investigated further, it can be hypothesised that it is regulated by c-FLIP, an apoptosis inhibitor, as in reovirus infection [27]. The control of caspase-8 by c-FLIP could be regulated by the activity of MAPK p38 [31,32], which has been shown to play a role in BTV-induced apoptosis and endothelial damage [33,34]. …”

Section: Discussionmentioning

confidence: 99%

Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

Stewart

Roy

2010

Virol J

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BackgroundBluetongue virus (BTV) infection causes haemorrhagic disease in ruminants and induces cell death. The pathogenesis in animals and in cell culture has been linked to BTV-induced apoptosis.ResultsIn this report, we investigated BTV-induced apoptosis in cell culture in depth and show that both extrinsic (caspase-8 activation) and intrinsic (caspase-9 activation) pathways play roles in BTV apoptosis. Further, by using chemical inhibitors and knock-out cell lines, we show that these pathways act independently of each other in BTV infected cells. In addition to activation of caspase-8, -9 and executioner caspase-3, we also identified that BTV infection causes the activation of caspase-7, which results in the cleavage of poly (ADP-ribose) polymerase (PARP). BTV-induced cell death appears to be due to apoptosis rather than necrosis, as the HMBG-1 was not translocated from the nucleus. We also examined if NF-κB response is related to BTV-induced apoptosis as in reovirus. Our data suggests that NF-κB response is not linked to the induction of apoptosis. It is controlled by the degradation of only IκBα but not IκBβ, resulting in a rapid transient response during BTV infection. This was supported using an NF-κB dependent luciferase reporter gene assay, which demonstrated early response, that appeared to be suppressed by the late stage of BTV replication. Furthermore, virus titres were higher in the presence of NF-κB inhibitor (SN50), indicating that NF-κB has a role in initiating an antiviral environment. In addition, we show that BTV infection induces the translocation of interferon regulatory factors (IRF-3 and IRF-7) into the nucleus. The induction of IRF responses, when measured by IRF dependent luciferase reporter gene assay, revealed that the IRF responses, like NF-κB response, were also at early stage of infection and mirrored the timing of NF-κB induction.ConclusionBTV triggers a wide range of caspase activities resulting in cell apoptosis. Although both NF-κB and IRF responses are induced by BTV infection, they are not sustained.

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Section: Discussionmentioning

confidence: 99%

Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

Stewart

Roy

2010

Virol J

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“…JNK is termed a stress-activated protein kinase (SAPK) and was shown to be activated in reovirus-infected cells (31,33). To probe if EHDV2-IBA infection involves JNK activation, lysates of OK cells either noninfected or infected with EHDV2-IBA were separated by SDS-PAGE at different time points and subjected to immunoblotting with anti-total-JNK (tJNK) and anti-phospho-JNK (pJNK) antibodies (Fig.…”

Section: Ehdv Induces Apoptosismentioning

confidence: 99%

“…Specifically, JNK activation mediates the apoptosis induced by BTV (31) and, depending on the strain, by MRV (32,33). Similarly, different strains of MRV also differ in their potentials to induce and benefit from integrated cell stress responses (34).…”

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confidence: 99%

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Shai

Schmukler

Yaniv

et al. 2013

J Virol

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The mode and timing of virally induced cell death hold the potential of regulating viral yield, viral transmission, and the severity of virally induced disease. Orbiviruses such as the epizootic hemorrhagic disease virus (EHDV) are nonenveloped and cytolytic. To date, the death of cells infected with EHDV, the signal transduction pathways involved in this process, and the consequence of their inhibition have yet to be characterized. Here, we report that the Ibaraki strain of EHDV2 (EHDV2-IBA) induces apoptosis, autophagy, a decrease in cellular protein synthesis, the activation of c-Jun N-terminal kinase (JNK), and the phosphorylation of the JNK substrate c-Jun. The production of infectious virions decreased upon inhibition of apoptosis with the pan-caspase inhibitor Q-VD-OPH (quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone), upon inhibition of autophagy with 3-methyladenine or via the knockout of the autophagy regulator Atg5, or upon treatment of infected cells with the JNK inhibitor SP600125 or the cyclin-dependent kinase (CDK) inhibitor roscovitine, which also inhibited c-Jun phosphorylation. Moreover, Q-VD-OPH, SP600125, and roscovitine partially reduced EHDV2-IBA-induced cell death, and roscovitine diminished the induction of autophagy by EHDV2-IBA. Taken together, our results imply that EHDV induces and benefits from the activation of signaling pathways involved in cell stress and death.T he epizootic hemorrhagic disease virus (EHDV) is an arbovirus (genus orbiviruses) of the Reoviridae family that is transmitted by biting midges and infects ruminants. In recent years, outbreaks of epizootic hemorrhagic disease in cattle have been reported in Israel and Turkey (1, 2), suggesting that EHDV is an emerging threat to the cattle industry in Europe (3). EHDV presents structural and sequence similarities to the better-studied bluetongue virus (BTV), sharing its repertoire of infection targets and symptoms of disease (3, 4). However, in spite of structural similarities between these viruses, a recent study suggests that preexisting immunity to BTV does not protect against EHDV infection (5). The EHDV genome is organized in 10 double-stranded RNA (dsRNA) segments encoding seven structural proteins (VP1 to VP7) and the nonstructural (NS) proteins NS1 to NS3. Recently, an additional nonstructural protein, NS4, has been identified in BTV (6, 7), raising the possibility that the same protein occurs in EHDV. The present study mainly employs the Ibaraki strain of EHDV2 (EHDV2-IBA), originally isolated from infected cattle in 1959, in Ibaraki, Japan (8). Selected experiments were also carried out with EHDV7-Israel (EHDV7-ISR), isolated from infected cattle in 2006 in Israel (1).For different types of reoviruses, including BTV, apoptosis is integral to the cellular pathogenesis they induce (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Yet the molecular mechanisms that govern reovirus-mediated induction of apoptosis are a contentious matter (10,17,19,20). For orbiviruses in general and EHDV in partic...

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“…Furthermore, some viruses such as herpes simplex virus type 1 and rotavirus can manipulate the JNK signaling pathway to regulate viral replication (McLean and Bachenheimer, 1999;Holloway and Coulson, 2006). The p38 MAPK signaling pathway is activated to induce apoptosis by bluetongue virus, soft-shelled turtle iridovirus, and other viruses as well as to control viral replication by viruses such as coxsackievirus B3 and varicella-zoster virus (Mortola and Larsen, 2010;Huang et al, 2011;Si et al, 2005;Rahaus et al, 2004). In case of severe acute respiratory syndrome-coronavirus, p38 MAPK induces cell death in Vero E6 cells and JNK is related to persistent infection (Mizutani et al, 2004(Mizutani et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Jun N-terminal kinase by Akabane virus is required for apoptosis

Mitomo

Omatsu

Tsuchiaka

et al. 2016

Research in Veterinary Science

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Akabane virus (AKAV) belongs to the Simbu serogroup of the genus Orthobunyavirus in the family Bunyaviridae. It has been shown that AKAV induces apoptosis in mammalian cells. It is necessary to understand the signaling pathways involved in AKAV-induced apoptosis to further elucidate the molecular virology of AKAV. c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) are mediators of apoptosis; therefore, we investigated the roles of JNK and p38 MAPK cascades in AKAV-infected cells. We found that JNK and p38 MAPK as well as their downstream substrates, c-Jun and heat shock protein 27 (HSP27), were phosphorylated in response to AKAV infection. A JNK inhibitor (SP600125) inhibited AKAV-mediated apoptosis whereas a p38 MAPK inhibitor (SB203580) did not. We conclude that AKAV infection activates the JNK and p38 MAPK signaling pathways, and the JNK cascade plays a crucial role in AKAV-induced apoptosis in vitro.

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Bluetongue virus infection: Activation of the MAP kinase-dependent pathway is required for apoptosis

Cited by 10 publications

References 28 publications

Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Activation of c-Jun N-terminal kinase by Akabane virus is required for apoptosis

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