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ABSTRACT: We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca(2+)) concentration in neuroblastoma IMR5 cells, at least partly through Ca(2+) release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP(3)R) and ryanodine receptor (RyR) channels. This leads to Ca(2+) accumulation in mitochondria through the mitochondrial Ca(2+) uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca(2+) concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.
Journal of Virology 12/2010; 84(23):12226-35. · 5.40 Impact Factor
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ABSTRACT: Mitochondria are dynamic organelles and can undergo regulated fission/fragmentation to produce smaller organelles or, alternatively, can undergo fusion to produce tubular or net-like mitochondrial structures. Although some of the molecules that control mitochondrial fission and fusion are known, new molecules and pathways that control this process continue to be discovered, suggesting that this process is more complex than previously appreciated. In addition to their crucial role in the regulation of apoptosis, recent studies have implicated members of the Bcl-2 family in maintenance of the mitochondrial network. Here, we discuss the mechanisms governing mitochondrial fission/fusion and summarize current knowledge concerning the role of Bcl-2 family members in regulating mitochondrial fission/fusion dynamics.
Cellular and Molecular Life Sciences CMLS 02/2010; 67(10):1599-606. · 6.57 Impact Factor
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ABSTRACT: Bcl-2 family proteins regulate apoptosis by controlling the release of mitochondrial cytochrome c via the Bax/Bak channel. However, recent studies have also implicated several members of this family in the regulation of mitochondrial fission/fusion dynamics. It has been debated whether the role of Bcl-2 proteins in mitochondrial morphogenesis is functionally distinct from their role in apoptosis, with some arguing that Bax/Bak-induced mitochondrial fission promotes apoptosis-associated cytochrome c release, while others suggest that these functions are separable. Here we review this emerging area and argue for a role for the Bcl-2 family as novel regulators of mitochondrial morphogenesis.
Molecular cell 11/2009; 36(3):355-63. · 14.61 Impact Factor
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ABSTRACT: The flaccid paralyses characteristic of poliomyelitis are a direct consequence of the infection of motor neurons with poliovirus (PV). In PV-infected mice, motor neurons die by apoptosis. However, the mechanisms by which PV induces cell death in neurons remain unclear. Analyses of the apoptotic pathways induced by PV infection in several cell lines have demonstrated that mitochondria play a key role in PV-induced apoptosis. Furthermore, mitochondrial dysfunction results from an imbalance between pro- and anti-apoptotic pathways. We present here an overview of the many studies of PV-induced apoptosis carried out in recent years and discuss the contribution of these studies to our understanding of poliomyelitis.
Frontiers in Bioscience 02/2009; 14:2181-92. · 3.52 Impact Factor
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ABSTRACT: Human enteroviruses are among the most common viruses infecting humans. These viruses are known to be able to infect a wide range of tissues and are believed to establish persistent infections. Enteroviruses are positive-sense single-stranded RNA viruses whose replication involves the synthesis of negative strand intermediates. Therefore, the specific detection of negatively stranded viral RNA in tissues or cells is a reliable marker of active enteroviral replication. The present report presents the development of a real-time RT-PCR allowing the specific detection and quantification of negatively stranded viral RNA. Since it was known that specific amplification of single-stranded RNA can be made difficult by false-priming events leading to false-positive or overestimated results, the assay was developed by using a tagged RT primer. This tagged RT-PCR was shown to be able to amplify specifically negative RNA of enteroviruses grown in cell cultures by preventing the amplification of cDNAs generated by false-priming.
Journal of Virological Methods 09/2008; 153(2):182-9. · 2.01 Impact Factor
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ABSTRACT: Poliovirus (PV)-induced apoptosis seems to play a major role in tissue injury in the central nervous system (CNS). We have previously shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. We showed here that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, limiting the extent of JNK activation and thereby cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the apoptosis signal-regulating kinase 1, which acts upstream from JNK in PV-infected IMR5 cells. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in the CNS.
Journal of Virology 05/2008; 82(7):3796-802. · 5.40 Impact Factor
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ABSTRACT: Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH(2)-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.
Journal of Virology 08/2007; 81(14):7504-16. · 5.40 Impact Factor
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ABSTRACT: Rotaviruses are the leading cause of infantile viral gastroenteritis worldwide. Mature enterocytes of the small intestine infected by rotavirus undergo apoptosis, and their replacement by less differentiated dividing cells probably leads to defective absorptive function of the intestinal epithelium, which, in turn, contributes to osmotic diarrhea and rotavirus pathogenesis. Here we show that infection of MA104 cells by the simian rhesus rotavirus strain RRV induced caspase-3 activation, DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase; all three phenomena are features of apoptosis. RRV induced the release of cytochrome c from mitochondria to the cytosol, indicating that the mitochondrial apoptotic pathway was activated. RRV infection of MA104 cells activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change. Most importantly, Bax-specific small interfering RNAs partially inhibited cytochrome c release in RRV-infected cells. Thus, mitochondrial dysfunction induced by rotavirus is Bax dependent. Apoptosis presumably leads to impaired intestinal functions, so our findings contribute to improving our understanding of rotavirus pathogenesis at the cellular level.
Journal of Virology 06/2007; 81(9):4457-64. · 5.40 Impact Factor
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Florence Colbère-Garapin,
Sandra Martin-Latil,
Bruno Blondel,
Laurence Mousson,
Isabelle Pelletier, Arnaud Autret,
Alan François,
Violeta Niborski,
Gianfranco Grompone,
Guillaume Catonnet,
Ariane van de Moer
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ABSTRACT: The structure and function of the intestinal epithelium is briefly described, with the principal mechanisms involved in diarrhea. Human enteric viruses and probiotics are presented. We then review how probiotic bacteria could interfere with virus-induced pathology, we present our own view and describe specific interactions that would be valuable targets for future studies.
Microbes and Infection 9(14-15):1623-31. · 3.10 Impact Factor
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ABSTRACT: Le poliovirus est l'agent responsable de la poliomyélite paralytique aigüe. Les paralysies flasques caractéristiques de la poliomyélite résultent de la destruction des neurones moteurs, les cellules cibles spécifiques du poliovirus dans le système nerveux central (SNC). Le développement de nouveaux modèles animaux et cellulaires a permis d'étudier les étapes clés de la pathogénèse de la poliomyélite à un niveau moléculaire. En particulier il a été montré chez la souris que l'induction de l'apoptose est un élément important de l'atteinte du SNC des animaux paralysés suite à l'infection par le poliovirus. Dans cette revue, la biologie moléculaire du poliovirus et la pathogénèse de la poliomyélite paralytique seront décrites brièvement et plusieurs modèles d'apoptose induite par le poliovirus avec son récepteur cellulaire dans l'apoptose sera également considéré.
