Enterovirus 71-Induced Neurological Disorders in Young Gerbils, Meriones unguiculatus: Development and Application of a Neurological Disease Model

Abstract

A reliable disease model mimicking Enterovirus 71 (EV71) infection in humans is essential for understanding pathogenesis and for developing a safe and effective vaccine. Commonly used rodent models including mouse or rat models are not suitable for vaccine evaluation because the rodents are resistant to EV71 infection after they reach the age of 6 days. In this study, 21-day-old gerbils inoculated intraperitoneally (IP) with a non mouse-adapted EV71 strain developed neurological lesion-related signs including hind limb paralysis, slowness, ataxia and lethargy similar to those of central nervous system (CNS) infection of EV71 in humans. The infected gerbils eventually died of the neurological lesions and EV71 could be isolated from lung, liver, spleen, kidney, heart, spinal cord, brain cortex, brainstem and skeletal muscle. Significantly high virus replication was detected in spinal cord, brainstem and skeletal muscle by cellular analysis, real-time quantitative PCR (RT-PCR) and immunohistochemical staining. Histopathologic changes such as neuronal degeneration, neuronal loss and neuronophagia were observed in spinal cord, brain cortex, brainstem, and skeletal muscle along with necrotizing myositis and splenic atrophy. Gerbils that received two doses of inactive whole-virus vaccine showed no EV71-specific symptoms after challenged with EV71. In contrast, gerbils that received mock vaccination died of EV71-induced neuropathology after challenged with EV71. The result indicates that gerbils can serve as a reliable disease model for evaluating safety and efficacy of EV71 vaccine.

Global Transcriptomic Analysis of Human Neuroblastoma Cells in Response to Enterovirus Type 71 Infection

“…Additionally, angiomotin-like protein 2 (AMOTL2) and two other members of the motin family are the Yes-associated protein 1 (YAP1)-associated proteins, which regulate the expression of several proliferation- and apoptosis-related genes. It has been reported that AMOTL2 is essential for cell movements in vertebrate embryos [56] and serves as a scaffolding protein to regulate Wnt/β-catenin [7]. In addition, the phosphate cytidylyltransferase 2 ( PCYT2 ) gene was 3.5-fold up-regulated during EV71 infection in SH-SY5Y cells.…”

“…Mouse experiments revealed that EV71 invaded the CNS through retrograde axonal transport and that hematogenous transport represented only a minor route of transmission [4], [5], [6]. Histopathological changes, such as neuronal degeneration, neuronal loss and neuronophagia, were observed in the spinal cord, brainstem, and skeletal muscle, along with necrotizing myositis and splenic atrophy, after gerbils were inoculated intraperitoneally with EV71 [7]. Additionally, radiological or histopathological evidence of the induction of paralysis, a similar process to that of poliovirus, was also observed during EV71 infection [8], [9], [10], [11].…”

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

“…In cases that resemble poliomyelitis, widespread neuronal necrosis is the dominant histopathological feature associated with the replication of this virus in neurons and results in the clinical manifestation of neurogenic paralysis (Whitton et al, 2005). Although several autopsy findings have suggested that EV71 may infect neurons and cause the neuronal degeneration observed in individual fatal HFMD cases (Khong et al, 2012; Yao et al, 2012), the mechanism underlying the neuronal pathogenesis in the CNS has not been described in the literature. This situation has raised the question of how the pathological progression caused by the EV71 infection leads to the severe clinical manifestations (such as neurogenic pulmonary edema and cardiopulmonary failure) that are responsible for the high case fatality rate (Chan et al, 2000; Wu et al, 2002).…”

Phylogenetic analysis of the Mongolian gerbil (Meriones unguiculatus) from China based on mitochondrial genome

“…M. unguiculatus infected with Helicobacter pylori mimic human H. pylori infection, facilitating the analysis of the underlying processes and the study of gastritis and gastric cancer (Wei et al, 2012). M. unguiculatus has also been used in studies of nutrition (Ying et al, 2013), aging (Ohlemiller, 2009), epilepsy (Heo and Kang, 2012), parasites (Conchedda et al, 2006), ethology (Moons et al, 2012), and viral infections (Yao et al, 2012). However, although it is an important experimental animal, the available genetic information on gerbils is very limited and its phylogenetic classification is uncertain.…”