Single-cell atlas of hepatitis C virus inoculated tree shrew liver reveals immune activation, metabolic reprogramming, and persistent inflammation

Sep 30, 2026

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Hepatitis C virus remains a major global health challenge due to limited animal models that faithfully reproduce disease biology. This study uses tree shrews with intrahepatic inoculation by the HCV JFH1 strain to profile molecular programs across distinct liver cell populations. Single-cell transcriptomic profiling at acute (1 week) and long-term (111 weeks) stages reveals interferon-stimulated gene induction across cell types, hepatocyte metabolic downshifts, impaired glucose metabolism, erythroblast presence only during acute infection, and neutrophil subclusters linked to NET formation.

LanguageEnglish

CategoryHealthcare

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Pages23

Reading Time58 min

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Articles Single-cell atlas of hepatitis C virus inoculated tree shrew liver reveals immune activation, metabolic reprogramming, and persistent inflammation Dandan Yu,a,b,c,g Wei-Bo Kang,a,c,g Yu-Hua Ma,b Long-Bao Lv,b Shihua Zhang,d Lei Tang,e Sheng Liu,e Jin Zhong,f,∗∗ and Yong-Gang Yaoa,b,c,∗ aState Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Yunnan Engineering Center on Brain Disease Models, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China bNational Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China cKunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China dState Key Laboratory of Mathematical Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China eState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510623, China fShanghai Institute of Immunity and Infection, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China Summary Background Hepatitis C virus (HCV) remains a major global health challenge, largely due to the absence of robust animal models that recapitulate this disease, hindering mechanistic studies and vaccine development. This study employed tree shrews to determine the molecular profiles of distinct liver cell populations following HCV infection. Methods Tree shrews received intrahepatic injections ofthe HCV JFH1 strain and were analysed at two timepoints: 1 week post-inoculation (acute) and 111 weeks post-inoculation (long-term) . Viral load was assessed up to 30 weeks. Liver pathology was assessed via haematoxylin and eosin (H&E) staining. Single-cell transcriptomic profiling was performed on liver tissues, while tree shrew primary hepatocytes and ITH6 hepatic cells, as well as human Huh7 cells, were used to characterise cellular changes following HCV infection. Findings Sixteen major cell types were identified in 157,298 liver cells across HCV-inoculated and control treeshrews. Acute inoculation triggered widespread induction of interferon-stimulated genes (ISGs) across all cell types, including the periportal ISGhigh hepatocyte subcluster, and concurrent reduction in metabolic gene expression in hepatocytes in vivo. Impaired glucose metabolism, as confirmed in HCV-exposed ITH6 cells, likely contributed to this metabolic shift. Erythroblasts were exclusively detected during acute inoculation and exhibited enhanced intercellular communication signatures. Among neutrophils, three distinct subclusters were identified, one of which displayed elevated expression of neutrophil extracellular trap (NET) markers and enhanced NET formation in inoculated livers. Interpretation This study provides a comprehensive single-cell transcriptomic landscape of HCV-inoculated tree shrew livers. These findings underscore the use of the tree shrew model for advancing mechanistic understanding of HCV pathogenesis, as well as its relevance for therapeutic and vaccine development. Funding This work was supported by grants from National Natural Science Foundation of China (U1902215, U25A20646), National Key Research and Development Plan Program (2022YFF0710900), Key Project of the CAS“Light of West China” Program (xbzg-zdsys-202302), and Yunnan Province (202305AH340006, 202001AS070023) . *Corresponding author. State Key Laboratory of Genetic Evolution and Animal Models, Key Laboratory of Animal Models a

FAQs

What animal model and viral strain were used to study HCV infection?

Tree shrews received intrahepatic injections of the HCV JFH1 strain.

When were samples analyzed to capture acute versus long-term effects?

Analyses were performed at two timepoints: 1 week post-inoculation (acute) and 111 weeks post-inoculation (long-term).

What major immune and metabolic changes were observed after acute inoculation?

Acute infection triggered widespread induction of interferon-stimulated genes across cell types and concurrent reduction of hepatocyte metabolic gene expression, with impaired glucose metabolism noted in HCV-exposed ITH6 cells.

Sep 30, 2026

Uploaded by Himbo