Abstract
Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.
Highlights
The hepatitis A virus (HAV) is one of the major causes of acute hepatitis [1,2,3], sometimes resulting in acute liver failure, leading to a transplant or even death [3,4]
We previously reported that a treatment of 5 μM zinc chloride for 72 h suppressed HAV genotype IIIA HA11-1299 replication by 62.2% compared with the untreated control in human hepatoma Huh7 cells [10]
The severity of the acute-on-chronic liver failure (ACLF) caused by acute hepatitis A may be associated with severe underlying chronic liver diseases, such as advanced liver fibrosis and cirrhosis [4,38]
Summary
The hepatitis A virus (HAV) is one of the major causes of acute hepatitis [1,2,3], sometimes resulting in acute liver failure, leading to a transplant or even death [3,4]. If hygiene and sanitation are continuously improved but low anti-HAV immunity is maintained, future hepatitis A outbreaks may occur in places like Japan [7,8]. It is important to develop antiviral drugs and to use HAV vaccines more widely. We and others have demonstrated that zinc compounds (zinc sulfate, zinc chloride, zinc oxide and zinc oxide nanoparticles) have anti-HAV properties [9,10,11]. Zinc sulfate inhibits HAV replication while enhancing the expression of glucose-regulated protein 78 (GRP78/Bip), an antiviral that impedes HAV [12,13] in a dose-dependent manner [9,10]. Zinc chloride inhibits HAV replication with or without interferon [10]
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