Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2018; 24(20): 2173-2180
Published online May 28, 2018. doi: 10.3748/wjg.v24.i20.2173
Effects of hepatitis E virus infection on interferon production via ISG15
Min Wang, Ying Huang, Man He, Wen-Ju Peng, De-Ying Tian
Min Wang, Man He, Wen-Ju Peng, De-Ying Tian, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Ying Huang, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510700, Guangdong Province, China
Author contributions: Wang M and Tian DY designed the research; Wang M, Huang Y, He M and Peng WJ performed the research; Tian DY contributed new reagents; Wang M and Tian DY analyzed the data; Wang M and Tian DY wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81570540.
Institutional review board statement: The study was reviewed and approved by the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board.
Conflict-of-interest statement: All authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: De-Ying Tian, PhD, Professor, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430030, Hubei Province, China.
Telephone: +86-15387019549 Fax: +86-21-64085875
Received: March 29, 2018
Peer-review started: March 30, 2018
First decision: April 11, 2018
Revised: April 19, 2018
Accepted: April 23, 2018
Article in press: April 23, 2018
Published online: May 28, 2018

To assess the effects of hepatitis E virus (HEV) on the production of type I interferons (IFNs) and determine the underlying mechanisms.


We measured the production of interferon (IFN)-alpha and -beta (-α/β) in genotype 3 HEV-infected C3A cells at different time points (0, 8, 12, 24, 48, 72 and 120 h) by enzyme-linked immunosorbent assay (ELISA). The expression levels of IFN-stimulated gene (ISG)15 in HEV-infected C3A cells at different time points were tested by western blotting. The plasmid-expressing open reading frame 3 (ORF3) or control plasmids (green fluorescent protein-expressing) were transfected into C3A cells, and the levels of IFN-α/β and ISG15 were evaluated, respectively. Furthermore, the plasmid-expressing ISG15 or small interfering RNA-inhibiting ISG15 was transfected into infected C3A cells. Then, the production of IFN-α/β was also measured by ELISA.


We showed that genotype 3 HEV could enhance the production of IFN-α/β and induce elevation of ISG15 in C3A cells. HEV ORF3 protein could enhance the production of IFN-α/β and the expression of ISG15. Additionally, ISG15 silencing enhanced the production of IFN-α/β. Overexpression of ISG15 resulted in the reduction of IFN-α/β.


HEV may promote production of IFN-α/β and expression of ISG15 via ORF3 in the early stages, and increased ISG15 subsequently inhibited the production of IFN-α/β.

Keywords: Open reading frame 3, Interferon-stimulated gene 15, Interferon-alpha, Hepatitis E virus, Interferon-beta

Core tip: To date, few studies have investigated the role of ISG15 in hepatitis E virus (HEV) infection and the impact of ISG15 on interferons (IFN) production. This study showed that HEV could inhibit the level of type I IFN through regulating the expression of IFN-stimulated gene (ISG)15, which may attenuate the IFN response, allowing for successful infection of their hosts. The present study enhances the understanding of the interaction between ISG15 and HEV in the host innate immune response, which may provide useful insight for the development of new antiviral drugs and antiviral strategies.