A small animal model of chronic hepatitis E infection using immunocompromised rats

• Published in: JHEP reports Vol. 4; no. 10; p. 100546
• Main Authors: Sridhar, Siddharth, Wu, Shusheng, Situ, Jianwen, Shun, Estie Hon-Kiu, Li, Zhiyu, Zhang, Anna Jin-Xia, Hui, Kyle, Fong, Carol Ho-Yan, Poon, Vincent Kwok-Man, Chew, Nicholas Foo-Siong, Yip, Cyril Chik-Yan, Chan, Wan-Mui, Cai, Jian-Piao, Yuen, Kwok-Yung
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2022; Elsevier
• Subjects: HEV; HEV-C1; Immunosuppression; Orthohepevirus C; Rat hepatitis E; Ribavirin; Rocahepevirus ratti; PBS; MMF; ALT; Ribavirin; VTM; rRT-PCR; Immunosuppression; IFN-γ; HEV-C1; Rocahepevirus ratti; HEV; Rat hepatitis E; LD; Orthohepevirus C; HEV-A; IC; dpi; HD
• ISSN: 2589-5559; 2589-5559
• DOI: 10.1016/j.jhepr.2022.100546

HEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV (Rocahepevirus ratti; 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. 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. 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 (p <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. We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients. 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. [Display omitted] •Chronic HEV infection is challenging to model with small animals.•Rats can be immunocompromised by transplant rejection drugs taken by patients.•This model supports chronic rat HEV infection robustly and consistently.•Immunosuppression in this model is scalable, reversible, and responsive to ribavirin.