Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits.

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE

Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.

Hepatitis E*/immunology ; Hepatitis E*/virology ; Hepatitis E*/drug therapy ; Hepatitis E virus*/immunology ; Immunosuppressive Agents*/pharmacology ; Immunosuppressive Agents*/therapeutic use ; Cyclosporine*/pharmacology ; Cyclosporine*/therapeutic use ; Disease Models, Animal* ; Immunosuppression Therapy* ; Tacrolimus*/pharmacology ; Tacrolimus*/therapeutic use; Animals ; Rabbits ; Prednisolone/therapeutic use ; Prednisolone/pharmacology ; Male ; Immunity, Innate/drug effects ; Mycophenolic Acid/pharmacology ; Hepatitis, Chronic/drug therapy ; Hepatitis, Chronic/immunology ; Hepatitis, Chronic/virology ; Chronic Disease ; Calcineurin Inhibitors/pharmacology ; Calcineurin Inhibitors/therapeutic use

Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL ) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.
Competing Interests: The authors declare no conflict of interest.

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2023YFC2306900 MOST | National Key Research and Development Program of China (NKPs); 82002143 MOST | National Natural Science Foundation of China (NSFC); YESS20210021 CAST | CAST Innovation Foundation; 88014Y0236, 88032Y0008 China Postdoctoral Foundation Project | Postdoctoral Research Foundation of China (China Postdoctoral Research Foundation)

Keywords: chronic infection; hepatitis E virus; immunosuppressant; rabbit model

0 (Immunosuppressive Agents)
83HN0GTJ6D (Cyclosporine)
WM0HAQ4WNM (Tacrolimus)
9PHQ9Y1OLM (Prednisolone)
HU9DX48N0T (Mycophenolic Acid)
0 (Calcineurin Inhibitors)

Date Created: 20240620 Date Completed: 20240723 Latest Revision: 20240725

20240726

PMC11264948

10.1128/jvi.00846-24

38899900