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.

Vaccine-derived polioviruses:collaboration with M. Rakoto-Andrianarivelo, R. Razafindratsimandresy,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. 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.

In collaboration with M. Roivainen and coll. (THL, Helsinki), we have shown thatgenetically highly divergent VDPVs isolated from sewage in Tampere, Finland, were neurovirulent. These VDPVs had characteristics similar to those of strains isolated from immunodeficient, persistently infected persons.

Poliovirus pathogenicity at the cellular level. PV-induced apoptosis seems to play a major role in tissue injury in the central nervous system. Signaling pathways are activated following PV-receptor interaction in human neuronal cells.We have shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. 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 also investigated the impact of cytosolic Ca²⁺increase on the cellular response in terms of mitochondrial function and apoptosis in human neuroblastoma cells following PV infection. We showed that PV-induced cytosolic Ca²⁺increase in IMR5 cells is due, at least in part to the release of Ca²⁺from the endoplasmic reticulum lumen. This leads to the accumulation of Ca²⁺in mitochondria, the induction of mitochondrial dysfunction and apoptosis.

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

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