A Small Animal Model of Chronic Hepatitis E Infection Using Immunocompromised Rats

Overview

Journal JHEP Rep

Specialty Gastroenterology

Date 2022 Sep 2

PMID 36052220

Authors

Siddharth Sridhar

Shusheng Wu

Jianwen Situ

Estie Hon-Kiu Shun

Zhiyu Li

Anna Jin-Xia Zhang

Kyle Hui

Carol Ho-Yan Fong

Vincent Kwok-Man Poon

Nicholas Foo-Siong Chew

Cyril Chik-Yan Yip

Wan-Mui Chan

Jian-Piao Cai

Kwok-Yung Yuen

Affiliations

Soon will be listed here.

Abstract

Background & Aims: HEV variants such as swine genotypes within species (HEV-A) and rat HEV (; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection.

Methods: In this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored.

Results: A high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats ( <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection.

Conclusions: We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients.

Lay Summary: Convenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans.

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