Biology of Enteric Viruses  


  HEADCOLBÈRE-GARAPIN Florence PhD / florence.colbere-garapin@pasteur.fr
  MEMBERSBALANANT Jean Engineer/ BESSAUD Maël PhD, Post-doc / BLONDEL Bruno PhD / Brisac Cynthia PhD student/ COLBÈRE-GARAPIN Florence PhD / DELPEYROUX Francis PhD / HOLMBLAT Barbara PhD student / Jegouic Sophie PhD student / Joffret Marie-Line PhD Engineer / MBOW Awa Laboratory assistant (50%) / PELLETIER-doucement Isabelle PhD Engineer / TEOULE François Master 2/ VALENCELLE Marie-Christine secretary (50%)


  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 diseases caused by HEVs involve viral attacks on 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 has allowed the emergence of pathogenic, vaccine-derived PV (VDPVs). We are studying the evolution and the biology of enteroviruses, in particular circulating VDPVs.

Emergence of recombinant VDPVs in Madagascar:collaboration with M. Rakoto-Andrianarivelo, J.M. Reynes and their colleagues, (IP Madagascar). Our results show the broad distribution of VDPVs in the Toliara province, and intense and rapid cocirculation and coevolution of the vaccine strains and other but related enterovirus strains. A short period with low vaccination coverage is enough to generate favorable conditions for the emergence of VDPVs. We have also shown that non-polio sequences present in an epidemic VDPV contribute to its characteristics, including its pathogenicity. We showed that these non-polio sequences are related to coxsackievirus A 17 (CA17) genomes. We also demonstrated that PV/CA17 recombinants are viable. The virus in which the 3' portion of the VDPV genome was replaced with the 3' half of the CA17 genome was almost as neurovirulent as the VDPV. The co-circulation in children and recombination of viruses, viruses differing in their pathogenicity for humans and in certain other biological properties such as receptor use, can lead to the generation of pathogenic recombinants. This constitutes a new mechanism of viral evolution and emergence.

We have also improved technologies to characterize the genome of enteroviruses, and developed a Taqman RT-PCR assay for the detection and quantification of negative-strand HEV RNA, a reliable marker of active enteroviral replication. In addition, we have contributed to several epidemiological studies on poliovirus circulation and evolution in Tunisia (H. Triki and coll.), West and Central Africa (I. Gouandjika-Vasilache and coll.) and Argentina (J.E. Mueller and coll.), and on rhinovirus evolution and recombination in China (V. Deubel and coll.).

Virus receptors and signaling pathways. Signaling pathways are activated following poliovirus-receptor interaction in human neuronal cells.PV-induced apoptosis seems to play a major role in tissue injury in the central nervous system. We have shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells (J. Estaquier and coll.). We have demonstrated 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. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in neurons.

We have also shown that anti-ICAM-1 antibodies can block CA17 infection, suggesting that ICAM-1 is a receptor for this virus, and investigated the role of class I human leukocyte antigen molecules in early steps of echovirus infection (F.A. Lemonnier and coll.).

*Following our evaluation by the AERES in 2009, the INSERM U994 Biology of enteric viruses(head F. Delpeyroux) was created.

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

colbere-garapin.jpg

The mitochondrial network in human neuroblastoma cells is stained green; nuclei are stained blue.



  Publications

- Jegouic S, Joffret ML, Blanchard C, Riquet FB, Perret C, Pelletier I, Colbere-Garapin F, Rakoto-Andrianarivelo M, Delpeyroux F. 2009. Recombination between polioviruses and co-circulating Coxsackie A viruses: role in the emergence of pathogenic vaccine-derived polioviruses. PLoS Pathog. May;5(5):e1000412. PMID: 19412342.

- Huang T, Wang W, Bessaud M, Ren P, Sheng J, Yan H, Zhang J, Lin X, Wang Y, Delpeyroux F, Deubel V. 2009. Evidence of recombination and genetic diversity in human rhinoviruses in children with acute respiratory infection. PLoS One. 2009 Jul 27;4(7):e6355.PMID: 19633719.

-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.

- 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.





Activity Reports 2009 - Institut Pasteur
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