Biology of Enteric Viruses  


  HEADDr COLBÈRE-GARAPIN Florence / florence.colbere-garapin@pasteur.fr
  MEMBERSDr AUTRET Arnaud / BALANANT Jean / Dr BESSAUD Maël / Dr BLONDEL Bruno / Brisac Cynthia / CAMPANARO Malika / Dr DELPEYROUX Francis / Jegouic Sophie / Dr Joffret Marie-Line / Dr PELLETIER-doucement Isabelle / 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 enteroviruses, in particular circulating VDPVs.

Genetic exchange between poliovirus and human enteroviruses C(Rakoto-Andrianarivelo M., Riquet F., Jegouic S., Bessaud, M., Joffret, M.L., Balanant J., Blanchard C., Guillot S., Vibet M.A., Blondel B., Rousset D., Razafindratsimandresy, R.,Reynes, J.M., Delpeyroux F). Pathogenic VDPV strains implicated in poliomyelitis epidemics in Madagascar in 2002 and 2005 have been investigated. Type 3 or type 2 VDPV was isolated in the Toliara province of Madagascar in 2005 from 5 poliomyelitis patients and from healthy contacts. These strains were classified into different recombinant lineages that showed complex mosaic genomic structures originating from different vaccine strain serotypes and probably from HEVs of the species C (HEV-C). Genetic relatedness could be observed among these 4 lineages. These results indicate intense and rapid cocirculation and coevolution of the vaccine strains and of their related HEV-C. To study the role of HEV-C sequences in the phenotype of VDPVs, we generated a series of recombinants between a Madagascar VDPV isolate and its parental vaccine PV strain. Results indicated that the HEV-C sequences present in this VDPV contribute to its characteristics, including pathogenicity. This suggests that inter-species recombination contributes to the phenotypic biodiversity of polioviruses and may favor the emergence of VDPVs(Rakoto-Andrianariveloand coll., PloS Pathogens, 2007 and Rakoto-Andrianariveloand coll., J. Infect. Diseases, 2008, Riquet and coll. J. Virol., 2008).

Signaling pathways activated following poliovirus-receptor interaction in human neuronal cells. (Autret, A. Brisac, C., Colbère-Garapin, F., & Blondel, B.). 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 have recently shown that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, inhibiting the extent of JNK activation, thereby limiting cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the signal-regulating kinase 1 (ASK1), 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. (Autret and coll., J. Virol., 2007 and Autret and coll., J. Virol., 2008).

Cure of persistent poliovirus infection by RNA interference. (Pelletier, I., Saulnier A. and Colbère-Garapin, F.). We have previously demonstrated the complete cure of persistently PV-infected cells by antiviral siRNAs (Saulnier and coll. Mol. Ther. 2006). The phenotype of cured cells is currently investigated.

Keywords: poliovirus, coxsackievirus A, apoptosis, survival pathways, signaling pathways, paralytic poliomyelitis

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Early phosphatidylinositol 3-kinase/Akt pathway activation limits poliovirus-induced JNK-mediated neuronal cell death



  Publications

- 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.

- Rakoto-Andrianarivelo M., Gumede, N., Jegouic, S., Balanant, J., Andriamamonjy, S., Rabemanantsoa, S., Birmingham, M., Randriamanalina, B., Nkolomoni, L., Venter, M., Schoub, B.D., Delpeyroux F. and J.M. Reynes. 2008. Reemergence of recombinant vaccine-derived poliovirus outbreak in Madagascar. The Journal of Infectious Diseases, 197, 1427-1435. PMID: 18419577.

- Autret A, Martin-Latil S, Brisac C, Mousson L, Colbère-Garapin F, Blondel B. 2008. Early phosphatidylinositol 3-kinase/Akt pathway activation limits poliovirus-induced JNK-mediated cell death. Journal of Virology, 82, 3796-3802. PMID: 18216097.

- Riquet, F., Blanchard, C., Jegouic, S., Balanant, J., Guillot, S., Vibet, M.A., Rakoto-Andrianarivelo, M. Delpeyroux, F. 2008. Impact of exogenous sequences on the characteristics of an epidemic type 2 recombinant vaccine-derived poliovirus. Journal of Virology, 82, 8927-8932. PMID: 18579607.





Activity Reports 2009 - Institut Pasteur
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