Mouse and Non-human Primate Models for EV71 Disease

Abstract

During the final stage of polio eradication in the Western Pacific Region (WPR) in the late 1990s, there have been large outbreaks of hand, foot and mouth disease (HFMD) due to enterovirus 71 (EV71) associated with severe neurological diseases. However, pathogenesis of EV71 infection is still poorly understood, in part, due to limited animal models to study the neurovirulence of EV71. Immediately after the identification of EV71 as one of most neurotropic enteroviruses, a non-human primate model for EV71 disease had been established in the 1970s. In response to recent EV71-aassociated HFMD outbreaks in the WPR, we have extended this non-human primate model to study the molecular basis of EV71 neurovirulence by using different genotypes of field EV71 isolates and genetically modified EV71 mutants derived from infectious molecular clones of EV71. By using the non-human primate model, we found that two major recent lineages of EV71 in the WPR, genogroups B and C, are considered to be neurovirulent, and we have analyzed the attenuation determinants and immunogenicity of EV71 for further vaccine development. The non-human primate model may provide more information on EV71 pathogenesis than previous mouse infection models. However, mouse models, using young mice and/or mouse-adapted EV71 variants, have been widely used to study the in vivo phenotypes of EV71 due to the limited availability of non-human primates. Thus, we have recently developed a novel mouse infection model using NOD/SCID mice and a mouse adapted EV71 variant, and confirmed the presence of the same attenuation determinants of EV71 both in non-human primate and mouse models. Although primate and mouse models would be still important to study the pathogenesis of EV71, identification of the cellular receptor and development of transgenic mice susceptible to EV71 may provide new insights into the molecular basis of EV71 infection in the near future.