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

Stewart, Meredith; Roy, Polly

doi:10.1186/1743-422x-7-362

Cited by 27 publications

(34 citation statements)

References 47 publications

(73 reference statements)

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“…These results are in agreement with those presented for orthoreovirus (Kominsky et al, 2002) and BTV (Nagaleekar et al, 2007), both of which activate the intrinsic apoptosis pathway following loss of mitochondrial membrane potential. However, these results differ from those reported for BTV in which DNA fragmentation is observed at 36 h post-infection and caspase-3 is activated at 24 h post-infection in virus-infected mammalian cells (Mortola et al, 2004;Stewart and Roy, 2010).…”

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confidence: 99%

African horse sickness virus induces apoptosis in cultured mammalian cells

2012

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Infection of mammalian cell cultures with African horse sickness virus (AHSV) is known to result in dramatic cytopathic effects (CPE), but no CPE is observed in infected insect cell cultures despite productive virus replication. The basis for this phenomenon has not yet been investigated, but is suggestive of apoptosis being induced following virus infection of the mammalian cells. To investigate whether AHSV can induce apoptosis in infected mammalian cells, Culicoides variipennis (KC) insect cells and BHK-21 mammalian cells were infected with AHSV-9 and analyzed for morphological and biochemical hallmarks of apoptosis. In contrast to KC cells, infection of BHK-21 cells with AHSV-9 resulted in ultrastructural changes and nuclear DNA fragmentation, both of which are associated with the induction of apoptosis. Results also indicated that AHSV-9 infection of BHK-21 cells resulted in activation of caspase-3, a key agent in apoptosis, and in mitochondrial membrane depolarization. Cumulatively, the data indicate that the intrinsic pathway is activated in AHSVinduced apoptosis.Keywords: African horse sickness virus; Apoptosis; BHK-21 cells; Culicoides variipennis cells; Caspases; Intrinsic pathwayAfrican horse sickness virus (AHSV) is a species in the genus Orbivirus, family Reoviridae (Calisher and Mertens, 1998), and is the causative agent of African horse sickness (AHS), a highly infectious arthropod-borne (Culicoides spp.) disease of equids, of which the mortality rate in horses may exceed 90% (Coetzer and Erasmus, 1994;Guthrie, 2007). Although African horse sickness virus (AHSV) causes severe oedema and haemorrhages in horses, it is asymptomatic in the insect host (Mellor and Hamblin, 2004;Wilson et al., 2009). This is also reflected in tissue culture where AHSV causes rapid cell death in infected mammalian cells in culture, whereas infection of insect cells are unapparent and show no CPE (Mirchamsy et al., 1970;Osawa and Hazrati, 1965). The basis for this differential host response is not known, but may be due to the induction of apoptosis in infected mammalian cells. Indeed, analyses of endothelial cells of animals infected with AHSV indicated ultrastructural changes that could be suggestive of apoptosis (Gómez-Villamandos et al., 1999).Apoptosis is a selective process of physiological cell deletion in response to numerous developmental and environmental stimuli (Kerr et al., 1972). There are two common pathways for the induction of apoptosis, i.e. the extrinsic pathway, which is primarily initiated by virus attachment to receptors, and the intrinsic pathway, which is mediated by damage to the mitochondria (Duprez et al., 2009). Various reports have indicated that infection of mammalian cells by viruses induces apoptosis (Roulston et al., 1999) and in some virus-induced diseases, apoptosis is a pathogenic mechanism that contributes in vivo to cell death, tissue injury and disease severity Samuel et al., 2007). Indeed, the induction of apoptosis has recently been implicated in the pathogenesis of bluetong...

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confidence: 99%

African horse sickness virus induces apoptosis in cultured mammalian cells

2012

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“…It is of great interest to investigate further whether a link exists between the determinants encoded by BTV that contribute to viral pathogenesis and the strength of IFN-␣/␤ signaling. It is also important to determine the putative role of some other viral proteins in the control of IFN-␣/␤ synthesis (48,60).…”

Section: Discussionmentioning

confidence: 99%

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Chauveau

Doceul

Lara

et al. 2012

J Virol

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Bluetongue virus (BTV), an arthropod-borne member of the Reoviridae family, is a double-stranded RNA virus that causes an economically important livestock disease that has spread across Europe in recent decades. Production of type I interferon (alpha/beta interferon [IFN-␣/␤]) has been reported in vivo and in vitro upon BTV infection. However, the cellular sensors and signaling pathways involved in this process remain unknown. Here we studied the mechanisms responsible for the production of IFN-␤ in response to BTV serotype 8. Upon BTV infection of A549 cells, expression of IFN-␤ and other proinflammatory cytokines was strongly induced at both the protein and mRNA levels. This response appeared to be dependent on virus replication, since exposure to UV-inactivated virus failed to induce IFN-␤. We also demonstrated that BTV infection activated the transcription factors IFN regulatory factor 3 and nuclear factor B. We investigated the role of several pattern recognition receptors in this response and showed that expression of IFN-␤ was greatly reduced after small-interfering-RNA-mediated knockdown of the RNA helicase encoded by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5). In contrast, silencing of MyD88, Toll-like receptor 3, or the recently described DexD/H-box helicase DDX1 sensor had no or a weak effect on IFN-␤ induction, suggesting that the RIG-I-like receptor pathway is specifically engaged for BTV sensing. Moreover, we also showed that overexpression of either RIG-I or MDA5 impaired BTV expression in infected A549 cells. Overall, this indicates that RIG-I and MDA5 can both contribute to the recognition and control of BTV infection.

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“…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 particular, these mechanisms and the functional consequences of apoptosis on the virus replication cycle remain uncharacterized and merit further study.…”

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confidence: 99%

“…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).…”

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

Cited by 27 publications

References 47 publications

African horse sickness virus induces apoptosis in cultured mammalian cells

African horse sickness virus induces apoptosis in cultured mammalian cells

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

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

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