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Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model

Zixue Shi1, Jianchao Wei1, Xufang Deng1, Shuqing Li2, Yafeng Qiu1, Donghua Shao1, Beibei Li1, Keyu Zhang1, Feiqun Xue1, Xiaodu Wang3 and Zhiyong Ma1*

Author Affiliations

1 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai 200241, PR China

2 Shanghai Entry-Exit Inspection and Quarantine Bureau, No. 1208, Minsheng Road, Shanghai 200135, PR China

3 Forestry and Biotechnology School, Zhejiang Agriculture and Forestry University, Lin’an, Hangzhou, China

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Virology Journal 2014, 11:10  doi:10.1186/1743-422X-11-10

Published: 23 January 2014

Abstract

Background

Japanese 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.

Methods

JEV-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.

Findings

NTZ 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.

Conclusions

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.

Keywords:
Japanese encephalitis virus; Nitazoxanide (NTZ); Antiviral