Abstract
Enterovirus 71 (EV71) is a key pathogen of hand, foot and mouth disease (HFMD) in children under 6 years of age. The antiviral potency of antioxidant isochlorogenic acid C (ICAC) extracted from foods was evaluated in cellular and animal models. First, the cytotoxicity of ICAC on Vero cells was investigated. The viral plaques, cytopathic effects and yield induced by EV71 infection were obviously reduced by ICAC, which was consistent with the investigation of VP1 transcripts and protein expression. Moreover, the mortality, weight loss and limb paralysis of mice caused by EV71 challenge were remarkably relieved by ICAC injection, which was achieved through decreases in the viral load and cytokine secretion in the mouse brain. Further biochemical assays showed that ICAC modulated several antioxidant enzymes involved in reduced and oxidized glutathione (GSH and GSSG) homeostasis, including glutathione reductase (GR), glutathione peroxidase (GPX), and glucose-6-phosphate dehydrogenase (G6PD), resulting in restoration of the GSH/GSSG ratio and reactive oxygen species (ROS) level. Finally, the antiviral effects of ICAC were dose-dependently disrupted by BSO, a biosynthesis inhibitor of GSH. This study indicated that ICAC acted as an antioxidant and prevented EV71 infection by modulating the redox homeostasis of glutathione.
Highlights
Human enterovirus 71 (EV71), which belongs to the genus Enterovirus, has been confirmed as a critical pathogen of hand, foot and mouth disease[1]
The data in this study indicated that Isochlorogenic acid C (ICAC) acted as an antioxidant and prevented Enterovirus 71 (EV71) infection via modulating GSH redox homeostasis
ICAC is a natural product from Lonicera japonica, which is a well-known traditional Chinese herb that is widely used in HFMD treatments[33]
Summary
Human enterovirus 71 (EV71), which belongs to the genus Enterovirus, has been confirmed as a critical pathogen of hand, foot and mouth disease[1]. EV71 infection can cause severe symptoms, such as pulmonary oedema and brainstem and cerebellar encephalitis, which can lead to respiratory failure and death[2,3,4,5] Cytokines in tissues, such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), can be induced by an excess viral load, resulting in tissue damage and chronic inflammation[6], which play key roles in the pathogenicity and severity of EV71 infection[7,8,9,10,11]. The viral infection could be reversed by supplementing with glutathione (GSH), which indicated roles for GSH in antiviral defence[16]. An imbalance in GSH redox homeostasis in host cells is observed[15] due to the accumulation of ROS18, which can be reversed by exogenous supplementation of antioxidants[15,16]. The potential regulation of GSH metabolism should be discussed with a focus on ICAC-derived inhibition of EV71 infection
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