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

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

doi:https://doi.org/10.1016/j.jcmgh.2024.101412

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

Shigeno, Satoshi; Kodama, Takahiro; Murai, Kazuhiro et al.

Cellular and Molecular Gastroenterology and Hepatology, 2025, 19(1), 101412

Number of Access:1,747（2025-07-18 13:09 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/98554

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Title	Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B
Creator	CreatorName Shigeno, Satoshi
	NRID 1000010623275 1000010623275 ORCID 0000-0002-6250-1324 0000-0002-6250-1324 researchmap permalink takahirokodama takahirokodama Scopus Author ID 35193885800 35193885800 CreatorName Kodama, Takahiro
	NRID 1000050867314 1000050867314 ORCID 0000-0001-8634-2922 0000-0001-8634-2922 researchmap permalink murai_kazuhiro murai_kazuhiro Scopus Author ID 57202460806 57202460806 CreatorName Murai, Kazuhiro
	NRID 1000010636830 1000010636830 researchmap permalink daisukem daisukem Scopus Author ID 35315737900 35315737900 CreatorName Motooka, Daisuke
	CreatorName Fukushima, Akihisa
	NRID 1000050934907 1000050934907 ORCID 0000-0003-1668-0779 0000-0003-1668-0779 researchmap permalink akira.nishio akira.nishio Scopus Author ID 57192072189 57192072189 CreatorName Nishio, Akira
	NRID 1000020623044 1000020623044 researchmap permalink hikitahayato hikitahayato Scopus Author ID 23667454900 23667454900 CreatorName Hikita, Hayato
	NRID 1000020397699 1000020397699 researchmap permalink read0140669 read0140669 Scopus Author ID 7202112131 7202112131 CreatorName Tatsumi, Tomohide
	NRID 1000080628595 1000080628595 researchmap permalink TOKAMOTO TOKAMOTO Scopus Author ID 10144905800 10144905800 CreatorName Okamoto, Toru
	NRID 1000080372613 1000080372613 CreatorName Kanto, Tatsuya
	NRID 1000070335355 1000070335355 researchmap permalink takeharatetsuo takeharatetsuo Scopus Author ID 7103332258 7103332258 CreatorName Takehara, Tetsuo
Subject	Chronic Hepatitis B
	HBV
	Immunocompetent
	Mouse Model
Description	Shigeno S., Kodama T., Murai K., et al. Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B. Cellular and Molecular Gastroenterology and Hepatology 19, 101412 (2025); https://doi.org/10.1016/j.jcmgh.2024.101412.
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.
Publisher	Elsevier Inc.
Source Title	Cellular and Molecular Gastroenterology and Hepatology
Volume (Issue)	19(1)
Page	101412
Date of Issued	2025-01-01
Language	English
Handle URL	https://hdl.handle.net/11094/98554
eISSN	2352345X
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.jcmgh.2024.101412
Access Rights	open access
CopyRight	© 2024. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Cellular and Molecular Gastroenterology and Hepatology. 2025, 19(1), p. 101412
DC.title	Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B
DC.creator	Shigeno, Satoshi
	Kodama, Takahiro
	Murai, Kazuhiro
	Motooka, Daisuke
	Fukushima, Akihisa
	Nishio, Akira
	Hikita, Hayato
	Tatsumi, Tomohide
	Okamoto, Toru
	Kanto, Tatsuya
	Takehara, Tetsuo
DC.publisher	Elsevier Inc.
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-01-01
DC.identifier	https://doi.org/10.1016/j.jcmgh.2024.101412
DC.subject	Chronic Hepatitis B
	HBV
	Immunocompetent
	Mouse Model
DC.description	Shigeno S., Kodama T., Murai K., et al. Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B. Cellular and Molecular Gastroenterology and Hepatology 19, 101412 (2025); https://doi.org/10.1016/j.jcmgh.2024.101412.
DCTERMS.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.
DC.rights	© 2024. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
DC.format	98554
citation_title	Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B
citation_author	Shigeno, Satoshi
	Kodama, Takahiro
	Murai, Kazuhiro
	Motooka, Daisuke
	Fukushima, Akihisa
	Nishio, Akira
	Hikita, Hayato
	Tatsumi, Tomohide
	Okamoto, Toru
	Kanto, Tatsuya
	Takehara, Tetsuo
citation_publisher	Elsevier Inc.
citation_language	English
citation_date	2025-01-01
citation_journal_title	Cellular and Molecular Gastroenterology and Hepatology
citation_volume	19
citation_issue	1
citation_firstpage	101412
citation_doi	https://doi.org/10.1016/j.jcmgh.2024.101412
citation_public_url	https://hdl.handle.net/11094/98554

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

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