Abstract
The pathogenesis of dengue virus (DV) infection has not been completely defined and change of redox status mediated by depletion of glutathione (GSH) in host cell is a common result of viral infection. Our previous study has demonstrated that DV serotype 2 (DV2) infection alters host intracellular GSH levels, and exogenous GSH inhibits viral production by modulating the activity of NF-κB in HepG2 cells. GSH is the most powerful intracellular antioxidant and involved in viral infections. Thus, this study was to investigate whether DV2 infection can induce alteration in redox balance and effect of GSH on the disease in HepG2 xenografts SCID mice. Our results revealed that mice infected with DV2 showed alterations in oxidative stress by increasing the level of malondialdehyde (MDA), an end product of lipid peroxidation, and GSSG/GSH ratio. DV2-infected mice also showed a decrease in the activity of catalase (CAT) and total superoxide dismutase (T-SOD) in the serum and/or observed organs, especially the liver. Moreover, DV2 infection resulted in elevated serum levels of the cytokines tumor necrosis factor-α and interlukin-6 and obvious histopathological changes in the liver. The administration of exogenous GSH significantly reversed all of the aforementioned pathological changes and prevented significant liver damage. Furthermore, in vitro treatment of HepG2 cells with antioxidants such as GSH inhibited viral entry as well as the production of reactive oxygen species in HepG2 cells. These results suggest that GSH prevents DV2-induced oxidative stress and liver injury in mice by inhibiting proinflammatory cytokine production, and GSH and may be a promising therapeutic agent for prevention of oxidative liver damage during DV infection.
Highlights
Dengue virus (DV) is a member of the family Flaviviridae and is one of the most widespread mosquito-borne human pathogens worldwide
Previous studies have suggested that reactive oxygen species (ROS)-induced oxidative stress as part of the host cell response to viral infections might play an important role in the pathogenesis of a variety of viral infections, including DV infection
To analyze whether antioxidants have inhibitory effects on the oxidative stress induced by DV infection in vivo, our previously developed mouse model was used with a slight modification that used i.p. injection of HepG2 cells into SCID mice rather than splenic injection [20]
Summary
Dengue virus (DV) is a member of the family Flaviviridae and is one of the most widespread mosquito-borne human pathogens worldwide. There are four antigenically distinct serotypes (DV1–4) based on differences in the envelope protein. A minority of patients may progress to lifethreatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) characterized by systemic hemorrhage and increased capillary permeability. DHF and DSS are often associated with an enlarged liver, jaundice, increased levels of transaminases and prolonged partial thromboplastin times, which indicate liver dysfunction and injury [1,2,3,4,5]. The proliferation of DV has been detected in vitro with apparent cytopathic effects (CPE) in different liver cell lines such as the human hepatocarcinoma cell line HepG2 [6]. Hepatocytes can support DV replication, and the liver is thought to be an important target organ for DV infection
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