Abstract
BackgroundJapanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk’ regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model.MethodsJEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated.FindingsNTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV.ConclusionsBoth in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.
Highlights
Japanese encephalitis virus (JEV) has a significant impact on public health
Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis
NTZ inhibits the JEV-induced cytopathic effect (CPE) To measure the cytotoxicity of NTZ to baby hamster kidney (BHK-21) cells that are susceptible to JEV infection, BHK-21 cells were treated with NTZ at various concentrations ranging from 0.1 to 32 μg/ml and incubated for 48 h
Summary
Japanese encephalitis virus (JEV) has a significant impact on public health. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. The anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model. Nitazoxanide (2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide) (NTZ) (Figure 1) is a thiazolide anti-infective, originally licensed in the United States (Alinia; Romark Laboratories, Tampa, FL, USA), for the treatment of parasitic enteritis caused by Cryptosporidium parvum and Giardia lamblia spectrum antiviral drug [11]. The mechanisms that underlie the antiviral activity of NTZ are not well understood. NTZ has been described to induce PKR (double-stranded-RNA-activated protein kinase) phosphorylation, which leads to the elevation of phosphorylated eIF2α eukaryotic translation initiation factor 2 alpha, an antiviral intracellular protein, in HCV-infected cells [14]. While in influenza virusinfected cells, NTZ prevents the maturation of viral hemagglutinin (HA) protein possibly by blocking HA trafficking between the endoplasmic reticulum and the Golgi complex [9]
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