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Antiviral and immune modulating effects of TLR7 agonist in a novel immunocompetent mouse model of chronic hepatitis B
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Satoshi Shigeno1,
Takahiro Kodama1,
Tetsuo Takehara1 |
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1Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine |
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| Background & Aims: We aimed to evaluate the antiviral and the intrahepatic immune modulating effects of IFNa and TLR7 agonist in the originally developed immunocompetent mouse model of chronic hepatitis B (CHB). 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 treatment with recombinant IFNa or the hepatotropic TLR7 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 number and cytotoxicity of mature NK cells also increased in CHB mice. IFNa and SA-5 treatment both resulted in viral suppression with mild hepatic flares in CHB mice. While both treatments activated NK cells, only SA-5 had the capacity to revitalize the impaired function of Tex cells and recruited macrophages. Conclusion: Our novel CHB mouse model recapitulated the intrahepatic exhausted antiviral immunity in CHB patients, which might be able to be reinvigorated by a hepatotropic TLR7 agonist. |
Index Term 1: chronic hepatitis B
Index Term 2: mouse model
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