Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71.

Pin Yu,Qi Lv,Wei Deng,Lili Xu,Fengdi Li,Chuan Qin,Linlin Bao,Yanfeng Xu

doi:10.3390/v9110351

Abstract

Enterovirus 71 (EV71) is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The aim of the study was to investigate the neurovirulence of EV71 strains and the differences in serum cytokine and chemokine levels in mouse models of severe and mild EV71 infection. Nine EV71 isolates belonging to the C4 subgenogroup (proposed as genotype D) displayed infectivity in human neuroblastoma SK-N-SH cells; moreover, ultrastructural observation confirmed viral particle replication. The survival rate of the severe model was 71.43% (5/7), and 60% (3/5) of the surviving severe model mice displayed sequelae of paralysis, whereas the only symptom in mild model mice was ruffled fur. Dynamic detection of serum cytokine and chemokine levels demonstrated that interleukin (IL)-5, IL-13, IL-6, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-C motif) ligand 5 (also called Regulated upon Activation, Normal T-cell Expressed, and Secreted (CCL5/RANTES) were significantly up-regulated at the early period of infection, indicating that these factors might herald a severe outcome. Our findings suggest that elevated cytokines and chemokines may have potential value as prognostic markers in mouse models.

Highlights

Enterovirus 71 (EV71) is one of the viral causes of hand, foot, and mouth disease (HFMD), a common, mild, and self-limiting pediatric disease characterized by skin or mucosal vesicles or rash [1,2]
In young children, HFMD associated with EV71 infection can cause serious complications, such as acute flaccid paralysis, myocarditis, aseptic meningitis, brainstem encephalitis, neurogenic pulmonary edema, and even death [2,3]
We examined the expression levels of the EV71 VP1 gene by real-time Reverse transcription (RT)-polymerase chain reaction (PCR) using VP1-specific primers, which confirmed that these nine clinical EV71 strains replicated in RD cells (Figure 1B)

Summary

Introduction

Enterovirus 71 (EV71) is one of the viral causes of hand, foot, and mouth disease (HFMD), a common, mild, and self-limiting pediatric disease characterized by skin or mucosal vesicles or rash [1,2]. In young children, HFMD associated with EV71 infection can cause serious complications, such as acute flaccid paralysis, myocarditis, aseptic meningitis, brainstem encephalitis, neurogenic pulmonary edema, and even death [2,3]. Enterovirus A of Picornaviridae; this family includes poliovirus, echovirus, and coxsackievirus [4]. The prototype EV71 strain BrCr was initially isolated from a patient with encephalitis who died in California, United States in 1969 [5,6]. Genotype A comprises one member, the prototype BrCr strain. Since the 1980s, EV71 epidemics have occurred in Asian countries, including outbreaks in Malaysia in 1997 [10], Taiwan in 1998 [11], Singapore in 2000 [12], and Japan

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