Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-09-28 DOI:10.1016/j.jcmgh.2024.101412

Satoshi Shigeno , Takahiro Kodama , Kazuhiro Murai , Daisuke Motooka , Akihisa Fukushima , Akira Nishio , Hayato Hikita , Tomohide Tatsumi , Toru Okamoto , Tatsuya Kanto , Tetsuo Takehara

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引用次数: 0

Abstract

Background & Aims

Targeting exhausted immune systems would be a promising therapeutic strategy to achieve a functional cure for HBV infection in patients with chronic hepatitis B (CHB). However, animal models recapitulating the immunokinetics of CHB are very limited. We aimed to develop an immunocompetent mouse model of CHB for intrahepatic immune profiling.

Methods

CHB mice were created by intrahepatic delivery of the Sleeping Beauty transposon vector tandemly expressing the hepatitis B virus (HBV) genome and fumarylacetoacetate hydrolase (FAH) cDNA into C57BL/6J congenic FAH knockout mice via hydrodynamic tail vein injection. We profiled the viral and intrahepatic immune kinetics in CHB mice with or without treatment with recombinant IFNα or the hepatotropic Toll-like receptor 7 agonist SA-5 using single-cell RNA-seq.

Results

CHB mice exhibited sustained HBV viremia and persistent hepatitis. They showed intrahepatic expansion of exhausted CD8+ T (Tex) cells, the frequency of which was positively associated with viral load. Recruited macrophages increased in number but impaired inflammatory responses in the liver. The cytotoxicity of mature natural killer (NK) cells also increased in CHB mice. IFNα and SA-5 treatment both resulted in viral suppression with mild hepatic flares in CHB mice. Although both treatments activated NK cells, SA-5 had the capacity to revitalize the impaired function of Tex cells and liver-recruited macrophages.

Conclusion

Our novel CHB mouse model recapitulated the intrahepatic exhausted antiviral immunity in patients with CHB, which might be able to be reinvigorated by a hepatotropic TLR7 agonist.

Abstract Image

查看原文本刊更多论文

慢性乙型肝炎免疫功能正常小鼠模型的肝内衰竭性抗病毒免疫。

背景与目的：以衰竭的免疫系统为靶点是一种很有前景的治疗策略，可实现对慢性乙型肝炎（CHB）患者 HBV 感染的功能性治愈。然而，能再现慢性乙型肝炎免疫动力学的动物模型非常有限。我们的目的是建立一种免疫功能正常的 CHB 小鼠模型，用于肝内免疫分析：CHB小鼠是通过向C57BL/6J先天性FAH基因敲除小鼠肝内注射串联表达乙型肝炎病毒（HBV）基因组和富马酸乙酰乙酸酯水解酶（FAH）cDNA的 "睡美人 "转座子载体制成的。我们利用单细胞 RNA-seq 分析了 CHB 小鼠在接受或不接受重组 IFNα 或肝脏 Toll 样受体 7 激动剂 SA-5 治疗时的病毒和肝内免疫动力学：结果：CHB小鼠表现出持续的HBV病毒血症和持续性肝炎。它们表现出肝脏内CD8+ T（Tex）细胞衰竭性扩增，其频率与病毒载量呈正相关。招募的巨噬细胞数量增加，但肝脏内的炎症反应却减弱了。CHB 小鼠成熟 NK 细胞的细胞毒性也有所增加。IFNα 和 SA-5 治疗均可抑制 CHB 小鼠的病毒，但肝脏会出现轻度发炎。虽然两种治疗方法都能激活NK细胞，但SA-5有能力恢复Tex细胞和肝脏募集巨噬细胞受损的功能：我们的新型慢性阻塞性肺病小鼠模型再现了慢性阻塞性肺病患者肝内衰竭的抗病毒免疫功能，这种免疫功能可能会被一种促肝TLR7激动剂重新激活。

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.