Delivery of Human EV71 Receptors by Adeno-Associated Virus Increases EV71 Infection-Induced Local Inflammation in Adult Mice

Hung-Bo Hsiao,Chia-Chyi Liu,Shu-Pei Lien,Mi-Hua Tao,Su-I Lin,Shih-Jen Liu,Pele Chong,Chih-Yeh Chen,Ai-Hsiang Chou

doi:10.1155/2014/878139

Abstract

Enterovirus71 (EV71) is now recognized as an emerging neurotropic virus in Asia and one major causative agent of hand-foot-mouth diseases (HFMD). However potential animal models for vaccine development are limited to young mice. In this study, we used an adeno-associated virus (AAV) vector to introduce the human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1) or a scavenger receptor class-B member-2 (hSCARB2) into adult ICR mice to change their susceptibility to EV71 infection. Mice were administered AAV-hSCARB2 or AAV-hPSGL1 through intravenous and oral routes. After three weeks, expression of human SCARB2 and PSGL1 was detected in various organs. After infection with EV71, we found that the EV71 viral load in AAV-hSCARB2- or AAV-hPSGL1-transduced mice was higher than that of the control mice in both the brain and intestines. The presence of EV71 viral particles in tissues was confirmed using immunohistochemistry analysis. Moreover, inflammatory cytokines were induced in the brain and intestines of AAV-hSCARB2- or AAV-hPSGL1-transduced mice after EV71 infection but not in wild-type mice. However, neurological disease was not observed in these animals. Taken together, we successfully infected adult mice with live EV71 and induced local inflammation using an AAV delivery system.

Highlights

Hand-foot-mouth diseases (HFMD) are mainly caused by Coxsackie virus (CV) and enterovirus71 (EV71) infections and have become serious public health problems in Asia
In order to characterize the function of these plasmids, L929 cells were transfected with pEMBL-CB-human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1) (Figure 1(b)) or pEMBL-CB-hSCARB2 (Figure 1(c)), and the surface expression of hPSGL1 or hSCARB2 were analyzed by using flow cytometry
These results suggested that the expression of hSCARB2 or hPSGL1 facilitates the infection with EV71

Summary

Introduction

Hand-foot-mouth diseases (HFMD) are mainly caused by Coxsackie virus (CV) and enterovirus (EV71) infections and have become serious public health problems in Asia. Brain stem related insufficiency was the primary injury in patients with neurological impairment [5, 6]. Neurogenic shock as a result of brain stem encephalitis has been proposed as the cause of pulmonary and cardiac complications [7]. In acute EV71 infections, massive IL1β, IL-6, IFNγ, and TNFα secretion was observed in the serum and cerebrospinal fluid in patients with brainstem encephalitis and pulmonary edema (PE), which demonstrated a significant correlation between proinflammatory cytokines and the disease severity [8, 9, 14, 15]. Several EV71 candidate vaccines are presently being developed and evaluated in human clinical trials [16]. There is no cost-effective and rapid animal model that can be used to evaluate the potential protection effect of these vaccine

Methods

Results

Conclusion