Mechanism for the lethal effect of enterovirus A71 intracerebral injection in neonatal mice

Min Feng,Yun Liao,Yang Gao,Guorun Jiang,Lichun Wang,Ying Zhang,Shengtao Fan,Xingli Xu,Qihan Li

doi:10.1038/s41374-019-0351-5

Abstract

Enterovirus A71 (EV-A71) infection is primarily responsible for fatal hand, foot, and mouth disease (HFMD) cases. Infants and younger children are more likely to suffer central nervous system damage as a result of EV-A71 infection, but this virus mostly does not affect older children and adults. This study investigated the possible mechanism underlying the age-dependent lethal effect of EV-A71 infection by comparing neonatal and adult mouse models of EV-A71 infection. Although viral proliferation is absent in both neonatal and adult mice, we observed that EV-A71, as a stimulus for astrocytes, elevates the levels of cytokines and monoamine neurotransmitters in neonatal mice. Then, we selected IL-6 and adrenaline as targets in a pharmacological approach to further validate the roles of these factors in mediating the mortality of neonatal mice after EV-A71 infection. Intracerebral injection of IL-6 and adrenaline enhanced the severity of EV-A71 infection, while treatment with an anti-IL-6-neutralizing antibody or the adrenergic-antagonist phenoxybenzamine reversed the lethal effect of EV-A71 in neonatal mice. These results suggest that the central nervous system (CNS) damage in neonatal cases of EV-A71 infection might be caused by an activated fetal cerebral immune response to the virus, including the disruption of brainstem function through increased levels of cytokines and neurotransmitters, rather than the typical cytopathic effect (CPE) of viral infection.

Highlights

Since 1997, hand, foot, and mouth disease (HFMD) has been an infectious disease that seriously affects the health of children in East and Southeast Asia [1, 2]
Astrocytes were involved in the lethal effect of EVA71 intracerebral injection in neonatal mice
The histopathological manifestations in the central nervous system (CNS) were characterized as glial cell proliferation and glial nodule formation, vascular congestion and lymphocytes infiltrates in the meninges, and partial cells located near ventricles that were swollen with a loose arrangement (Fig. 1c), and viral antigen was detected in the brainstem (Fig. 1d)

Summary

Introduction

Since 1997, hand, foot, and mouth disease (HFMD) has been an infectious disease that seriously affects the health of children in East and Southeast Asia [1, 2].

Methods

Results

Conclusion