Severity of enterovirus A71 infection in a human SCARB2 knock-in mouse model is dependent on infectious strain and route

Ning Chen,Changfa Fan,Kai Zheng,Yuxiao Zhang,Shuya Zhou,Chenfei Wang,Lin Sun,Junping Zhu,Lina Cao,Zhiyun Chen,Qiushui He,Xiaoyan Zhang,Qiaoyan Xiang

doi:10.1038/s41426-018-0201-3

Abstract

Enterovirus A71 (EV-A71) is a major etiological agent of human hand, foot and mouth disease, and it can cause severe neurological complications. Although several genotypes of EV-A71 strains are prevalent in different regions of the world, the genotype C4 has circulated in mainland China for more than 20 years. The pathogenicity of different EV-A71 clinical isolates varies and needs to be explored. In this study, hSCARB2 knock-in mice (N = 181) with a wide range of ages were tested for their susceptibility to two EV-A71 strains with the subgenotypes C4 and C2, and two infection routes (intracranial and venous) were compared. The clinical manifestations and pathology and their relationship to the measured viral loads in different tissues were monitored. We observed that 3 weeks is a crucial age, as mice younger than 3-week-old that were infected became extremely ill. However, mice older than 3 weeks displayed diverse clinical symptoms. Significant differences were observed in the pathogenicity of the two strains with respect to clinical signs, disease incidence, survival rate, and body weight change. We concluded that hSCARB2 knock-in mice are a sensitive model for investigating the clinical outcomes resulting from infection by different EV-A71 strains. The intracranial infection model appears to be suitable for evaluating EV-A71 neurovirulence, whereas the venous infection model is appropriate for studying the pathogenicity of EV-A71.

Highlights

Hand, foot and mouth disease (HFMD) is a common childhood disease, that is characterized by rapidly ulcerating vesicles in the mouth and vesicular lesions on the hands, feet, and buttocks
The disease severity induced by the strain CMU4232 in 3-week-old Human scavenger receptor class B member 2 (hSCARB2) KI mice was less than that caused by the strain clone-derived virus (CDV)-Isehara. These results suggested that these KI mice were susceptible to Enterovirus A71 (EV-A71) and that there was a difference in sensitivity of the hSCARB2 KI mice to the two strains
Based on the reliable EV-A71 disease model, we evaluated the pathogenicity of an endemic strain (CMU4232) in mainland China, and compared it with an internationally published strain (Isehara)[19]

Summary

Introduction

Foot and mouth disease (HFMD) is a common childhood disease, that is characterized by rapidly ulcerating vesicles in the mouth and vesicular lesions on the hands, feet, and buttocks. Enterovirus A71 (EV-A71) is a member of family Picornavieidae that is one of major etiological agent of HFMD and causes a variety of clinical manifestations including severe neurological complications including aseptic meningitis, brainstem encephalitis, neurogenic pulmonary edema, acute flaccid paralysis, and death[1,2,3]. In the Asian-Pacific region, EV-A71-related outbreaks have been reported frequently and are associated with increased neurovirulence and fatalities[5,6]. In mainland China, more than 600,000 HFMD cases and 126 deaths were reported in Fuyang City of Anhui province from March 2008 to June 2009. This outbreak spread quickly to other regions and caused nationwide HFMD epidemics. We have reported on the prevalence of EV-A71 during the HFMD epidemic in Beijing from 2007 to 2009, including

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Conclusion