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     Enterotropic viruses and antiviral strategies


  Director : Florence Colbère-Garapin (fcolbere@pasteur.fr)


  abstract

 

The topic of the laboratory concerns human enterotropic viruses and antiviral strategies, in particular RNA interference. Our project focuses on various aspects of the cellular response to viral infection, such as the resistance of cells to persistent viral infection and apoptosis. We are also studying emerging, circulating viruses, involved in recent poliomyelitis epidemics (PTR 120, leader : Francis Delpeyroux, collaboration between IP Paris and IP Madagascar). These viruses are recombinants between oral polio vaccine strains and cluster C enteroviruses.



  report

cale

Persistence of vaccine-derived polioviruses (F. Colbère-Garapin's group).

Immunodeficient patients whose gut is chronically infected by vaccine-derived poliovirus (VDPV) may excrete large amounts of virulent, mutated virus for years. To investigate how poliovirus (PV) establishes chronic infections in the gut, we tested whether it is possible to establish persistent VDPV infections in human intestinal cells. Four type 3 VDPV mutants, representative of the viral evolution in the gut of a hypogammaglobulinemic patient over almost two years (J. Martin et al., J. Virol., 2000, 74, 3001-10), were used to infect both undifferentiated, dividing cells, and differentiated, polarized enterocytes. A VDPV mutant excreted 36 days post-vaccination by the patient was lytic in both types of intestinal cell cultures, like the parental Sabin 3 strain. In contrast, three VDPVs, excreted 136, 442 and 637 days post-vaccination, established persistent infections both in undifferentiated cells and in enterocytes. Thus, viral determinants selected between day 36 and 136 conferred on VDPV mutants the capacity to infect intestinal cells persistently. The percentage of persistently VDPV-infected cultures was higher in enterocytes than in undifferentiated cells, implicating cellular determinants involved in the differentiation of enterocytes in persistent VDPV infections. The establishment of persistent infections in enterocytes was not due to poor replication of VDPVs in these cells, but was associated with reduced viral adsorption to the cellular receptor CD155.

Poliovirus-induced apoptosis (B. Blondel and T. Couderc, former "Neurovirologie et Régénération du Système Nerveux" Unit).

We have previously developed a mouse model susceptible to poliovirus infection and we have shown that poliovirus can persist in the central nervous system after the onset of paralysis throughout the life of animals. We have also shown that the poliovirus persistence could be due, at least in part, to an inhibition of viral genome synthesis in the central nervous system. During the acute phase of poliomyelitis, we have demonstrated that poliovirus kills motoneurons by an apoptotic process. We have recently developed a model of mixed mouse primary nerve cell cultures to study the molecular mechanisms of poliovirus-induced apoptosis in nerve cells. We have shown that poliovirus-induced apoptosis involved both activation of initiator caspases and mitochondrial dysfunctions. Moreover, the interactions of poliovirus with its cellular receptor (CD155) could modulate apoptosis and this modulation could play a role in poliovirus persistence. We are currently studying the molecular mechanisms involved in mitochondrial dysfunctions following poliovirus binding to CD155.

Keywords: Enterotropic viruses, neurotropic enterovirus, persistent infection, CD155, apoptosis



  publications

puce Publications 2003 of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
    Colbère-Garapin Florence, Chef de Laboratoire. fcolbere@pasteur.fr

Blondel Bruno, Chef de Laboratoire. bblondel@pasteur.fr
Labadie Karine, Ph.D student, Paris VI University

Saulnier Aure, Ph.D student, Paris VI University

Wirotius Aurélie, graduate student (DEA), Versailles

Pelletier-Doucement Isabelle, Research Engineer

Activity Reports 2003 - Institut Pasteur
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