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

Sridhar, Siddharth; Wu, Shusheng; Situ, Jianwen; Shun, Estie Hon-Kiu; Li, Zhiyu; Zhang, Anna Jinxia; 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

doi:10.1016/j.jhepr.2022.100546

Cited by 15 publications

(10 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The scope of rodent models, such as laboratory mice and rats, is highly limited for the study of HEV-A infection [23]. Rabbits and rats are small animal models currently available to study acute and chronic HEV infection, but they are only suitable to study rabbit variants of HEV-A genotype 3 and HEV-C1, respectively; human HEV-A genotypes 3 and 4 infections are limited in rabbits and absent in rats [20,24]. In contrast, Mongolian gerbils are a promising model to study acute infection with a broad range of HEV-A genotypes [25][26][27][28][29], as well as neurological manifestations of HEV-A infection [30,31].…”

Section: Introductionmentioning

confidence: 99%

Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils

Subramaniam,

Fares-Gusmao,

Sato

et al. 2023

PLoS Pathog

View full text Add to dashboard Cite

Hepatitis E virus (HEV) causes self-limited acute hepatitis in immunocompetent individuals and can establish chronic infection in solid organ transplant recipients taking immunosuppressive drugs. A well characterized small animal model is needed to understand HEV pathogenesis. In this study, we established a robust model to study acute and persistent HEV infection using Mongolian gerbils (Meriones unguiculatus) with or without immunosuppression. Gerbils were implanted subcutaneously with continuous release tacrolimus pellet to induce immunosuppression. Gerbils with or without tacrolimus treatment were inoculated with HEV intraperitoneally. Viremia, fecal virus shedding, serum antibody and ALT levels, liver histopathological lesions, hepatocyte apoptosis, and liver macrophage distribution were assessed. Mild to moderate self-limited hepatitis and IgM and IgG antibody responses against HEV ORF2 were observed in immunocompetent gerbils. Levels of HEV-specific IgM responses were higher and lasted longer in immunocompetent gerbils with higher peak viremia. Persistent viremia and fecal virus shedding with either weak, or absent HEV antibody levels were seen in immunosuppressed gerbils. Following HEV infection, serum ALT levels were increased, with lower and delayed peaks observed in immunosuppressed compared to immunocompetent gerbils. In immunocompetent gerbils, foci of apoptotic hepatocytes were detected that were distributed with inflammatory infiltrates containing CD68+ macrophages. However, these foci were absent in immunosuppressed gerbils. The immunosuppressed gerbils showed no inflammation with no increase in CD68+ macrophages despite high virus replication in liver. Our findings suggest adaptive immune responses are necessary for inducing hepatocyte apoptosis, CD68+ macrophage recruitment, and inflammatory cell infiltration in response to HEV infection. Our studies show that Mongolian gerbils provide a promising model to study pathogenesis during acute and persistent HEV infection.

show abstract

Section: Introductionmentioning

confidence: 99%

Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils

Subramaniam,

Fares-Gusmao,

Sato

et al. 2023

PLoS Pathog

View full text Add to dashboard Cite

show abstract

“…Such histological findings from diagnostic cases are common but are often attributed as non-specific changes. Preliminary findings from experimental infection of immunocompetent rabbit, pigs and wild boar, and immunosuppressed rat indicate the possibility of hepatocellular damage following inoculation [6, 51–53] and similar infiltration of inflammatory cells in periportal areas has also been described in rabbits in a later stage of infection [52]. In the ferret, experimental inoculation with FRHEV resulted in elevation of hepatic enzyme ALT during the acute phase of infection [10].…”

Section: Discussionmentioning

confidence: 93%

Subclinical hepatitis E virus infection in laboratory ferrets in the UK

Lean

Leblond

Byrne

et al. 2022

Journal of General Virology

View full text Add to dashboard Cite

Ferrets are widely used for experimental modelling of viral infections. However, background disease in ferrets could potentially confound intended experimental interpretation. Here we report the detection of a subclinical infection of ferret hepatitis E virus (FRHEV) within a colony sub-group of female laboratory ferrets that had been enrolled on an experimental viral infection study (non-hepatitis). Lymphoplasmacytic cuffing of periportal spaces was identified on histopathology but was negative for the RNA and antigens of the administered virus. Follow-up viral metagenomic analysis conducted on liver specimens revealed sequences attributed to FRHEV and these were confirmed by reverse-transcriptase polymerase chain reaction. Further genomic analysis revealed contiguous sequences spanning 79–95 % of the FRHEV genome and that the sequences were closely related to those reported previously in Europe. Using in situ hybridization by RNAScope, we confirmed the presence of HEV-specific RNA in hepatocytes. The HEV open reading frame 2 (ORF2) protein was also detected by immunohistochemistry in the hepatocytes and the biliary canaliculi. In conclusion, the results of our study provide evidence of background infection with FRHEV in laboratory ferrets. As this infection can be subclinical, we recommend routine monitoring of ferret populations using virological and liver function tests to avoid incorrect causal attribution of any liver disease detected in in vivo studies.

show abstract

“…Based on data from RHEV infection models in immunodeficient rats, nude mice, and Mongolian gerbils, viral loads generally increased and reached peak levels 14-18 days p.i. [28,29]. Therefore, in our study, samples were collected from infected A129 immunodeficient mice 14 days p.i.…”

Section: Discussionmentioning

confidence: 99%

“…RHEV strains can cause transient infection in laboratory rats [24,27]. Chronic infection models established in both nude mice and immunodeficient rats demonstrated clinical signs resembling those observed in immunocompromised HEV-infected human patients [28]. Recently, Mongolian gerbils (Meriones unguiculatus) were reported to be susceptible to HEV infection, exhibiting heterogeneous susceptibility to different HEV genotypes, and thus may represent a potential rodent model for in vivo studies of RHEV pathogenesis [29].…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of a novel rodent hepevirus in long-tailed dwarf hamsters (Cricetulus longicaudatus) in China

Xu,

Bie,

et al. 2024

Journal of General Virology

View full text Add to dashboard Cite

Hepeviruses have been identified in a broad range of animal hosts, including mammals, birds, and fish. In this study, rodents (n=91) from seven different species and ten pikas (Ochotona curzoniae) were collected in Qinghai Province, China. Using transcriptomic sequencing and confirmatory molecular testing, hepeviruses were detected in 27 of 45 (60 %) long-tailed dwarf hamsters (Cricetulus longicaudatus) and were undetected in other rodents and pika. The complete genome sequences from 14 representative strains were subsequently obtained, and phylogenetic analyses suggested that they represent a novel species within the genus Rocahepevirus, which we tentatively designated as Cl-2018QH. The virus was successfully isolated in human hepatoma (Huh-7) and murine fibroblast (17 Cl-1) cell lines, though both exhibited limited replication as assayed by detection of negative-sense RNA intermediates. A129 immunodeficient mice were inoculated with Cl-2018QH and the virus was consistently detected in multiple organs, despite relatively low viral loads. In summary, this study has described a novel rodent hepevirus, which enhances our knowledge of the genetic diversity of rodent hepeviruses and highlights its potential for cross-species transmission.

show abstract

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

Cited by 15 publications

References 39 publications

Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils

Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils

Subclinical hepatitis E virus infection in laboratory ferrets in the UK

Isolation and characterization of a novel rodent hepevirus in long-tailed dwarf hamsters (Cricetulus longicaudatus) in China

Contact Info

Product

Resources

About