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
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.
JHEP Rep. 2022 Aug 10;4(10):100546. doi: 10.1016/j.jhepr.2022.100546. eCollection 2022 Oct.
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.
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 ( <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.
戊型肝炎病毒（HEV）的一些变异株，如种内猪基因型（HEV-A）和大鼠HEV（HEV-C1），可在免疫功能低下个体中引起慢性戊型肝炎。目前几乎没有能准确反映慢性HEV感染的可靠且易于使用的小动物模型。我们旨在建立一种免疫功能低下的慢性戊型肝炎感染大鼠模型。
在这项动物模型感染研究中，用移植受者常用的药物组合（泼尼松龙、他克莫司和霉酚酸酯）对大鼠进行免疫抑制。用源自人和大鼠的HEV-C1毒株或源自人的HEV-A毒株对大鼠进行攻击。监测病毒载量、肝功能、肝脏组织学、体液和细胞免疫反应。
与低剂量（LD）免疫抑制剂处理的大鼠和免疫功能正常（IC）的大鼠中的短暂感染相比，高剂量（HD）免疫抑制方案持续延长了大鼠中源自人和大鼠的HEV-C1感染（感染后长达12周）。HD方案处理的大鼠粪便、血清和肝组织中的平均HEV-C1病毒载量高于LD或IC大鼠（P<0.05）。在慢性感染的大鼠中观察到丙氨酸氨基转移酶升高，这与肝组织学肝炎和肝组织中HEV-C1抗原表达一致。在物种特异性免疫印迹中，HD方案处理的大鼠无一（0/6）产生针对HEV-C1的抗体，LD方案处理的大鼠中有5/6产生抗体，IC大鼠中有6/6产生抗体。免疫抑制的逆转与HD方案处理的大鼠中病毒血症的清除以及HEV-C1特异性体液和细胞免疫反应的恢复相关，类似于慢性戊型肝炎治疗患者的模式。腹腔注射利巴韦林治疗可观察到病毒载量受到抑制。HD方案处理的大鼠对HEV-A感染仍不敏感。
我们建立了一种可扩展的免疫抑制大鼠慢性戊型肝炎模型，该模型在移植受者中紧密模拟了这种感染表型。
研究人类慢性戊型肝炎需要方便的小动物模型。我们通过用人类预防器官移植排斥常用的药物抑制大鼠的免疫反应，建立了一种慢性戊型肝炎动物模型。该模型紧密模拟了人类慢性戊型肝炎的特征。
