Biology of Enteric Viruses  


  HEADDr COLBÈRE-GARAPIN Florence / fcolbere@pasteur.fr
  MEMBERSAUTRET Arnaud / BALANANT Jean / Dr BESSAUD Maël / Dr BLONDEL Bruno / CAMPANARO Malika / Dr DELPEYROUX Francis / Jegouic Sophie / Dr Joffret Marie-Line / Dr MARTIN-LATIL Sandra
Dr PELLETIER-doucement Isabelle / MOUSSON Laurence / RIBIERRE Hélène


  Annual Report

Human enteroviruses (HEVs) belong to the Picornaviridaefamily that is one of the most important groups of human and animal pathogens. Virus multiplication in the intestine is generally asymptomatic, and the most serious acute pathologies caused by HEVs are diseases of the central nervous system. They include paralytic poliomyelitis, most cases of which are caused by poliovirus (PV). Massive anti-polio immunization programs have greatly reduced the prevalence of poliomyelitis worldwide. However, the disease has not been eradicated and low vaccine coverage in some developing countries allows the emergence of pathogenic, vaccine-derived PV (VDPVs). We are studying the evolution and the biology of enteric viruses, in particular circulating VDPVs.

Genetic exchange between PV and coxsackie A viruses(Rakoto-Andrianarivelo M., Guillot S., Iber J., Balanant J., Blondel B., Riquet F., Martin J., Kew O., Randriamanalina B., Razafinimpiasa L., Rousset D., Delpeyroux F). Pathogenic VDPV strains implicated in poliomyelitis epidemics in Madagascar in 2002 and 2005 have been investigated. The emergence of these VDPVs is associated with complex genetic recombination between PV and coxsakievirus A strains that belong to the same phylogenetic group of HEVs. To investigate in more details genetic interactions among HEVs, we looked for other cVDPVs and HEVs in stools collected in 2002 from healthy children living in the small area where most of the polio cases occurred.Several coxsackieviruses A17 and A13 carried nucleotide sequences closely related to the nonstructural protein encoding regions of the cVDPVs, suggesting common viral ancestors.The genetic exchanges between PV and coxsackieviruses contribute to the phenotypic diversity and possibly to the pathogenicity of VDPVs. There is evidence for an unexpectedly extensive diversity of coxsackievirus serotypes and genotypes in small human populations in some tropical regions, favoring genetic exchanges with PV(Rakoto-Andrianariveloand coll., PloS Pathogens, 2007 and Rakoto-Andrianariveloand coll., J. Infect. Diseases, in press).

Signaling pathways involved in PV-induced apoptosis in human neuronal cells. (Autret, A., Martin-Latil, S., Mousson L., Wirotius, A., Petit, F., Arnoult, D., Colbère-Garapin, F., Estaquier, J.& Blondel, B.). Mechanisms by which PV induces cell death in motor neurons remain unclear. We have demonstrated that PV infection of neuronal cells induces mitochondrial outer membrane permeabilization. PV infection also activates Bax, a pro-apoptotic member of the Bcl-2 family. Neutralization of Bax prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. We also found that c-Jun NH2-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 inhibits Bax activation and cytochrome c release. This demonstrates JNK-mediated Bax-dependent apoptosis in PV-infected neuronal cells, and shed some light on the molecular mechanisms of poliomyelitis pathogenesis(Autret and coll., J. Virol., 2007).

Keywords: poliovirus, coxsackievirus A, rotavirus, apoptosis, signaling pathways

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JNK-mediated Bax-dependent apoptosis in poliovirus-infected neuronal cells



  Publications

Signaling pathways involved in rotavirus-induced apoptosis in human epithelial cells. (Martin-Latil S., Mousson L., Autret A., Colbère-Garapin F., & Blondel B.) The role of Bcl-2 family members in rotavirus-induced apoptosis has been demonstrated, and this may participate to the mechanisms of rotavirus-induced gastroenteritis (Martin-Latil and coll.,J. Virol., 2007).

- Rousset, D., Rakoto-Andrianarivelo, M., Razafindratsimandresy, R., Randriamanalina, B., Guillot, S., Balanant, J., Mauclere, P., and Delpeyroux, F. 2003. Recombinant vaccine-derived poliovirus in Madagascar. Emerging Infectious Diseases, 9, 885-887. PMID: 12899139

- Saulnier, A., Pelletier, I., Labadie, K. & Colbère-Garapin, F.2006. Complete cure of persistent virus infections by antiviral siRNAs. Molecular Therapy, 13, 142-150. PMID: 16157509

- Martin-Latil S., Mousson L., Autret A., Colbère-Garapin F., & Blondel B. 2007. Bax is activated during rotavirus-induced apoptosis through the mitochondrial pathway. Journal of Virology, 81, 4457-4464. PMID: 17301139

- Autret, A., Martin-Latil, S., Mousson L., Wirotius, A., Petit, F., Arnoult, D., Colbère-Garapin, F., Estaquier, J.& Blondel, B. 2007. Poliovirus induces Bax-dependent cell death mediated by c-Jun NH2-terminal kinase. Journal of Virology, 81, 7504-7516. PMID: 17494073

- Rakoto-Andrianarivelo M., Guillot S., Iber J., Balanant J., Blondel B., Riquet F., Martin J., Kew O., Randriamanalina B., Razafinimpiasa L., Rousset D., Delpeyroux F. 2007. Co-circulation and evolutionof polioviruses and species C enteroviruses in a district of Madagascar. PLoS Pathogens, 3, e191. PMID: 18085822





Activity Reports 2007 - Institut Pasteur
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