The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice

Qing-Qing Ma; Hong-Jiang Wang; Jian Li; Meng-Qi Li; Tian-Shu Cao; Xiao-Yan Wu; Hong-Ying Qiu; Hui Zhao; Cheng-Feng Qin

doi:10.1016/j.virs.2022.07.009

October 2022

. doi: 10.1016/j.virs.2022.07.009

Citation: Qing-Qing Ma, Hong-Jiang Wang, Jian Li, Meng-Qi Li, Tian-Shu Cao, Xiao-Yan Wu, Hong-Ying Qiu, Hui Zhao, Cheng-Feng Qin. The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice .VIROLOGICA SINICA, 2022, 37(5) : 740-745. http://dx.doi.org/10.1016/j.virs.2022.07.009

甲型肝炎病毒减毒活疫苗H2株对I型干扰素受体缺陷小鼠的传染性和致病性

马青青 ^a ,
王洪江 ^b ,
李剑 ^a,c ,
李梦琪 ^a ,
曹天舒 ^a ,
吴晓燕 ^a ,
仇洪影 ^a ,
赵慧 ^a,, ,
秦成峰 ^a,d,,

军事科学院军事医学研究院微生物流行病研究所

通讯作者： 赵慧, shuishu2002@126.com; 秦成峰, qincf@bmi.ac.cn
收稿日期： 2022-04-22
录用日期： 2022-05-23

摘要

甲型肝炎病毒（HAV）减毒活疫苗H2株已被批准用于临床几十年，在非人灵长类模型和人类中具有理想的安全性。最近，I型干扰素（IFN）受体缺陷的小鼠被证明对HAV感染敏感。在此，我们试图确定在缺乏I型IFN受体的Ifnar^-/-小鼠中HAV H2的感染和复制动态。静脉注射H2后Ifnar^-/-小鼠的临床症状不明显，血清谷丙转氨酶（ALT）未见明显上调。值得注意的是，组织病理学检查显示，门静脉区有明显的局灶性淋巴细胞和中性粒细胞浸润，但肝组织无局灶性坏死，病毒RNA在肝内持续存在，感染病毒可从活组织中恢复到42天。更重要的是，H2感染可引起明显的病毒血症和持续的病毒在粪便中脱落。此外，在Ifnar^-/-小鼠中诱导了较强的甲型肝炎特异性体液免疫反应。总之，我们的研究明确了H2在Ifnar^-/-小鼠体内的安全性，这不仅有助于了解H2的衰减机制，也拓展了Ifnar^-/-小鼠模型在HAV研究中的应用。
- 甲型肝炎病毒
- , 甲肝
- , 减毒活疫苗
- , Ifnar^-/-小鼠
- , 感染特征

The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice

a State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, 100071, China;

Corresponding author: Hui Zhao, shuishu2002@126.com Cheng-Feng Qin, qincf@bmi.ac.cn
Received Date: 22 April 2022
Accepted Date: 23 May 2022

Abstract

Hepatitis A virus (HAV) live-attenuated vaccine H2 strain has been approved for clinical use for decades with ideal safety profiles in nonhuman primate models and humans. Recently, type I interferon (IFN) receptor-deficient mice were shown to be susceptible to HAV infection. Herein, we sought to determine the infection and replication dynamics of the H2 in Ifnar^-/- mice that lack type I IFN receptor. Following intravenous injection, the H2 failed to cause obvious clinical symptoms in Ifnar^-/- mice, and no significant upregulation in serum alanine aminotransferase (ALT) levels was observed. Notably, the histopathological examination showed that there were significant focal infiltrations of lymphocytes and neutrophils in the portal area, but no focal necrosis was observed in liver tissues. Viral RNAs sustained in the liver, and the infectious virus could be recovered from the liver tissue until 42 days post-infection. More importantly, H2 infection induced obvious viremia and persistent viral shedding in feces. In addition, robust HAV-specific humoral immune responses were induced in Ifnar^-/- mice. Overall, our study revealed the safety profile of H2 in Ifnar^-/- mice, which not only helps understand the attenuation mechanism of H2, but also expands the application of the Ifnar^-/-^-/- mouse model for HAV studies.
- Hepatitis A virus (HAV)
- , Hepatitis A
- , Mouse model
- , Live-attenuated vaccine

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Electronic Supplementary Material

10.1016j.virs.2022.07.009-ESM.docx