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

      research-article
      Author(s): 1 , 2 , 3 , ∗ , † , 1 , † , 1 , † , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 3 , 4
      Publication date (Electronic):
      Journal: JHEP Reports
      Publisher: Elsevier
      Keywords: HEV, Rat hepatitis E, HEV-C1, Ribavirin, Immunosuppression, Orthohepevirus C, Rocahepevirus ratti, ALT, alanine aminotransferase, dpi, days post infection, HD, high dose, HEV, hepatitis E virus, HEV-A, Paslahepevirus balayani, HEV-C1, Rocahepevirus ratti genotype 1, IC, immunocompetent, IFN-γ, interferon-γ, LD, low dose, MMF, mycophenolate mofetil, PBS, phosphate buffered saline, rRT-PCR, real-time reverse-transcription PCR, VTM, virus transport medium

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          Abstract

          Background & Aims

          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.

          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 ( 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.

          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.

          Graphical abstract

          Highlights

          • •

            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.

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          Most cited references39

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          EASL Clinical Practice Guidelines on hepatitis E virus infection

          Darius Moradpour, Nassim Kamar, Sally A. Baylis … (2018)
          Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4).
          Article 0 comments Cited 135 times – based on 0 reviews     Review now
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            Hepatitis E virus and chronic hepatitis in organ-transplant recipients.

            Jean-Michel Mansuy, Nathalie Danjoux, Florence Abravanel … (2008)
            Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed. Copyright 2008 Massachusetts Medical Society.
            Article 0 comments Cited 131 times – based on 0 reviews     Review now
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              Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants.

              Anne-Marie Roque-Afonso, Filomena Conti, Robert Santella … (2011)
              Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Siddharth Sridhar
                Journal
                Journal ID (nlm-ta): JHEP Rep
                Journal ID (iso-abbrev): JHEP Rep
                Title: JHEP Reports
                Publisher: Elsevier
                ISSN (Electronic): 2589-5559
                Publication date PMC-release: 10 August 2022
                Publication date Collection: October 2022
                Publication date (Electronic): 10 August 2022
                Volume: 4
                Issue: 10
                Electronic Location Identifier: 100546
                Affiliations
                [1 ]Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
                [2 ]State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
                [3 ]Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China
                [4 ]The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China
                Author notes
                [∗ ]Corresponding author. Address: Department of Microbiology, 19/F T-Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. Tel.: +852-2255-2408; Fax: +852-2855-1241.. sid8998@ 123456hku.hk
                [†]

                These first authors contributed equally to this manuscript.

                Article
                Publisher Item ID: S2589-5559(22)00118-5 Publisher ID: 100546
                DOI: 10.1016/j.jhepr.2022.100546
                PMC ID: 9424580
                PubMed ID: 36052220
                SO-VID: ef2cc376-5a71-496d-b91a-c695367971d3
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 8 February 2022
                Date revision received : 30 June 2022
                Date accepted : 8 July 2022
                Categories
                Subject: Research Article

                Keywords: hev,rat hepatitis e,hev-c1,ribavirin,immunosuppression,orthohepevirus c,rocahepevirus ratti,alt, alanine aminotransferase,dpi, days post infection,hd, high dose,hev, hepatitis e virus,hev-a, paslahepevirus balayani,hev-c1, rocahepevirus ratti genotype 1,ic, immunocompetent,ifn-γ, interferon-γ,ld, low dose,mmf, mycophenolate mofetil,pbs, phosphate buffered saline,rrt-pcr, real-time reverse-transcription pcr,vtm, virus transport medium
                Data availability:
                Keywords: hev, rat hepatitis e, hev-c1, ribavirin, immunosuppression, orthohepevirus c, rocahepevirus ratti, alt, alanine aminotransferase, dpi, days post infection, hd, high dose, hev, hepatitis e virus, hev-a, paslahepevirus balayani, hev-c1, rocahepevirus ratti genotype 1, ic, immunocompetent, ifn-γ, interferon-γ, ld, low dose, mmf, mycophenolate mofetil, pbs, phosphate buffered saline, rrt-pcr, real-time reverse-transcription pcr, vtm, virus transport medium

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