Cell‐type‐specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B

Author:

Wang Jun1234,Li Qian12,Qiu Yuanwang3,Kitanovski Simo4,Wang Chen1,Zhang Chenxia3,Li Fahong5,Li Xiaoguang3,Zhang Zhenfeng6,Huang Lihua3,Zhang Jiming5,Hoffmann Daniel4,Lu Mengji123,Lu Hongzhou1ORCID

Affiliation:

1. National Clinical Research Center for Infectious Diseases The Third People's Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and Technology Shenzhen China

2. Institute of Virology, University Hospital of Essen University of Duisburg‐Essen Essen Germany

3. Clinical Medical Research Center, The Fifth People's Hospital of Wuxi Jiangnan University Wuxi China

4. Bioinformatics and Computational Biophysics, Faculty of Biology and Center for Medical Biotechnology (ZMB) University of Duisburg‐Essen Essen Germany

5. Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Department of Infectious Diseases National Medical Center for Infectious Diseases, Shanghai Institute of Infectious Diseases and Biosecurity, Huashan Hospital Fudan University Shanghai China

6. School of Public Health and Emergency Management Southern University of Science and Technology Shenzhen China

Abstract

AbstractFunctional cure for chronic hepatitis B (CHB) remains challenging due to the lack of direct intervention methods for hepatic inflammation. Multi‐omics research offers a promising approach to understand hepatic inflammation mechanisms in CHB. A Bayesian linear model linked gene expression with clinical parameters, and population‐specific expression analysis (PSEA) refined bulk gene expression into specific cell types across different clinical phases. These models were integrated into our analysis of key factors like inflammatory cells, immune activation, T cell exhaustion, chemokines, receptors, and interferon‐stimulated genes (ISGs). Validation through multi‐immune staining in liver specimens from CHB patients bolstered our findings. In CHB patients, increased gene expression related to immune cell activation and migration was noted. Marker genes of macrophages, T cells, immune‐negative regulators, chemokines, and ISGs showed a positive correlation with serum alanine aminotransferase (ALT) levels but not hepatitis B virus DNA levels. The PSEA model confirmed T cells as the source of exhausted regulators, while macrophages primarily contributed to chemokine expression. Upregulated ISGs (ISG20, IFI16, TAP2, GBP1, PSMB9) in the hepatitis phase were associated with T cell and macrophage infiltration and positively correlated with ALT levels. Conversely, another set of ISGs (IFI44, ISG15, IFI44L, IFI6, MX1) mainly expressed by hepatocytes and B cells showed no correlation with ALT levels. Our study presents a multi‐omics analysis integrating bulk transcriptomic, single‐cell sequencing data, and clinical data from CHB patients to decipher the cause of intrahepatic inflammation in CHB. The findings confirm that macrophages secrete chemokines like CCL20, recruiting exhausted T cells into liver tissue; concurrently, hepatocyte innate immunity is suppressed, hindering the antiviral effects of ISGs.

Funder

China Postdoctoral Science Foundation

Publisher

Wiley

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