Animal models of enterovirus 71 infection: applications and limitations

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.

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

“…Previously, single mutations (G145E, E145Q, and K244E) in the conserved, positively charged 5-fold region of the VP1 capsid protein were identified as important sites for mouse adaptation of EV71 (13,14). Those studies used very young, 2-week-old ICR and 5-day-old BALB/c mice and also 3-to 4-week-old immunocompromised NOD/SCID mice (13,14).…”

“…Those studies used very young, 2-week-old ICR and 5-day-old BALB/c mice and also 3-to 4-week-old immunocompromised NOD/SCID mice (13,14). However, the mechanism by which these changes contribute to adaptation remains unknown.…”

“…However, the mechanism by which these changes contribute to adaptation remains unknown. Adaptive mutations were also identified in other regions of the EV71 genome (5= UTR, VP2, and 2C), but the roles they play in the increased virulence in mice were not determined (13). Previously, we adapted EV71 for growth in mice by passage in interferon receptor-deficient mice (15).…”

In Vivo Imaging with Bioluminescent Enterovirus 71 Allows for Real-Time Visualization of Tissue Tropism and Viral Spread

“…Our data revealed a range of EV71 infections in mice, from asymptomatic to severe. Before our studies, adult BALB/c mice were considered resistant to EV71 infection (9). However, we demonstrated that these mice had relatively high viral loads in many tissues and serum and expressed luciferase for several weeks after being infected with mEV71-NLuc.…”

EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines

“…Epidemiological surveys, ethical considerations and economic analyses are required to further support the rationale for a multivalent HFMD vaccine. The lack of appropriate animal models has so far been a hurdle in the evaluation of vaccine potency [22]. The use of chimpanzees is prohibited for both ethical and financial reasons but the engineering of transgenic mice expressing the EV71/CVA16 SCARB2 receptor represents a very promising approach in future pre-clinical studies [23].…”