Animal models of enterovirus 71 infection: applications and limitations.

Ya-Fang Wang,Chun-Keung Yu

doi:10.1186/1423-0127-21-31

Abstract

Human enterovirus 71 (EV71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the Asia-Pacific region over the past 15 years. Appropriate animal models are needed to understand EV71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. Non-human primate models have been used to characterize and evaluate the neurovirulence of EV71 after the early outbreaks in late 1990s. However, these models were not suitable for assessing the neurovirulence level of the virus and were associated with ethical and economic difficulties in terms of broad application. Several strategies have been applied to develop mouse models of EV71 infection, including strategies that employ virus adaption and immunodeficient hosts. Although these mouse models do not closely mimic human disease, they have been applied to determine the pathogenesis of and treatment and prevention of the disease. EV71 receptor-transgenic mouse models have recently been developed and have significantly advanced our understanding of the biological features of the virus and the host-parasite interactions. Overall, each of these models has advantages and disadvantages, and these models are differentially suited for studies of EV71 pathogenesis and/or the pre-clinical testing of antiviral drugs and vaccines. In this paper, we review the characteristics, applications and limitation of these EV71 animal models, including non-human primate and mouse models.

Highlights

Since the effective control of poliovirus, enterovirus 71 (EV71) has been regarded as the most important neurotropic enterovirus
EV71 infection is generally mild and self-limited, but occasionally such infection leads to central nervous system (CNS) infections that include aseptic meningitis, brainstem encephalitis and acute flaccid paralysis [6,7]
The infected-animals do not develop vesicular lesions on the skin and exhibit neither reduced muscle tension in the limbs nor typical neurological symptoms. These results suggest that, in addition to neurotropism, EV71 elicits respiratory tract tropism in rhesus monkeys; these observations contrast with those based on cynomolgus monkeys and mice

Summary

Introduction

Since the effective control of poliovirus, enterovirus 71 (EV71) has been regarded as the most important neurotropic enterovirus. Subsequent study [38] and our unpublished observations demonstrated that the mouse-adapted EV71/MP4 strain displayed strong neurotropism and was capable of consistently infecting and producing diseases that included brain infection, flaccid paralysis, pulmonary dysfunction and death in mice up to 14 days of age following intraperitoneal, intramuscular, intracranial, or oral inoculation. To overcome the bias of the natural tropism of mouseadapted/muscle-adapted strains, Khong et al [34] successfully infected 2-week-old AG129 mice with a non-mouse adapted EV71 strain (a clinical isolate termed 5865/SIN/ 00009) In these immunodeficient mice, the virus exhibited strong neurotropism and induced neurological manifestations after intraperitoneal and oral routes of inoculation. This finding raises the possibility of developing transgenic cows or goats for the mass production of lactoferrin-enriched milks and provides an evidence base that encourages breast-feeding in humans

Conclusion

11. Melnick JL

85. Brock JH