Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells

Background & Aims: The role of hepatocytes in producing chemokines and triggering liver inflammation and damage in chronic hepatitis D (CHD) is not fully understood. Herein, we investigated the contribution of primary human hepatocytes (PHHs) infected with HDV in triggering inflammation by p...

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Main Authors: Jan-Hendrik Bockmann, Lena Allweiss, Annika Volmari, David da Fonseca Araújo, Matin Kohsar, Anastasia Hyrina, Janine Kah, Zhijuan Song, Josolyn Chan, Katja Giersch, Tassilo Volz, Marc Lütgehetmann, Jeffrey J. Wallin, Dmitry Manuilov, Meghan M. Holdorf, Simon P. Fletcher, Ansgar W. Lohse, Antonio Bertoletti, Julian Schulze zur Wiesch, Maura Dandri
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Language:English
Published: Elsevier 2025-03-01
Series:JHEP Reports
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Online Access:http://www.sciencedirect.com/science/article/pii/S2589555924002775
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author Jan-Hendrik Bockmann
Lena Allweiss
Annika Volmari
David da Fonseca Araújo
Matin Kohsar
Anastasia Hyrina
Janine Kah
Zhijuan Song
Josolyn Chan
Katja Giersch
Tassilo Volz
Marc Lütgehetmann
Jeffrey J. Wallin
Dmitry Manuilov
Meghan M. Holdorf
Simon P. Fletcher
Ansgar W. Lohse
Antonio Bertoletti
Julian Schulze zur Wiesch
Maura Dandri
author_facet Jan-Hendrik Bockmann
Lena Allweiss
Annika Volmari
David da Fonseca Araújo
Matin Kohsar
Anastasia Hyrina
Janine Kah
Zhijuan Song
Josolyn Chan
Katja Giersch
Tassilo Volz
Marc Lütgehetmann
Jeffrey J. Wallin
Dmitry Manuilov
Meghan M. Holdorf
Simon P. Fletcher
Ansgar W. Lohse
Antonio Bertoletti
Julian Schulze zur Wiesch
Maura Dandri
author_sort Jan-Hendrik Bockmann
collection DOAJ
description Background & Aims: The role of hepatocytes in producing chemokines and triggering liver inflammation and damage in chronic hepatitis D (CHD) is not fully understood. Herein, we investigated the contribution of primary human hepatocytes (PHHs) infected with HDV in triggering inflammation by producing the chemokines CXCL9–11. Methods: We performed quantitative PCR, RNA in situ hybridisation, activation-induced marker (AIM) assays, and FACS analysis to investigate the CXCR3/CXCL9–11 receptor/ligand axis of T cells in peripheral blood and livers from patients with chronic hepatitis B (n = 27 and 18, respectively) and CHD (n = 20 and 18, respectively). Chemokine expression was investigated in cultured HDV-infected PHHs and in livers of HBV- or HBV/HDV-infected humanised mice in the presence or absence of adoptively transferred human immune cells (n = 35 in total). Results: In patient and chimeric mouse livers, higher expression levels of CXCL9–11 were found in an HBV/HDV-coinfected vs. HBV-mono-infected setting. Similarly, high levels of CXCL9–11 were observed in HDV-infected PHHs in vitro. Analysis by RNA in situ hybridisation on patient livers revealed that HDV-infected hepatocytes were a significant contributor to the chemokine expression. The corresponding chemokine receptor CXCR3 was found upregulated specifically on peripheral bulk CD4 T cells of patients with CHD. CXCR3 upregulation was unspecific and was not detected on HDAg- or HBsAg-specific CD4 T cells by activation-induced marker assay. Lastly, adoptive transfer of human T cells in humanised mice led to recruitment of non-HBV/HDV-specific CD4+ T cells only in the setting of HBV/HDV coinfection, but not in HBV-mono-infected mice. Conclusions: HDV infection upregulated the intrahepatic expression of the CXCL9–11/CXCR3 receptor/ligand axis. Higher amounts of HBV/HDV-unspecific CD4 T cells expressing CXCR3 may contribute to the aggravated liver inflammation frequently observed in patients with CHD. Impact and implications: Chronic hepatitis D (CHD) causes the most severe form of viral hepatitis, and treatment options are still limited; therefore, a more precise understanding of CHD immunopathology is needed. In this study, we demonstrated that HDV infection triggers CXCL9–11 expression in hepatocytes and liver infiltration of CXCR3-expressing CD4 T cells in preclinical models as well as patient biopsies. Because recruitment of Th1-polarised CD4 T cells to the liver has been also described for other severe liver diseases, such as autoimmune hepatitis, it may represent an important mechanism of aggravating liver diseases. The data of this study set hereby the basis for future studies analysing phenotype and function of intrahepatic T cells in CHD.
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spelling doaj-art-524845915ff54b2783f4da712462af332025-02-03T04:16:51ZengElsevierJHEP Reports2589-55592025-03-0173101273Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cellsJan-Hendrik Bockmann0Lena Allweiss1Annika Volmari2David da Fonseca Araújo3Matin Kohsar4Anastasia Hyrina5Janine Kah6Zhijuan Song7Josolyn Chan8Katja Giersch9Tassilo Volz10Marc Lütgehetmann11Jeffrey J. Wallin12Dmitry Manuilov13Meghan M. Holdorf14Simon P. Fletcher15Ansgar W. Lohse16Antonio Bertoletti17Julian Schulze zur Wiesch18Maura Dandri19Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, Germany; Corresponding author. Address: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel.: +49 40 7410 55662; fax: +49 40 7410 58531.Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Center for Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, GermanyGilead Sciences, Foster City, CA, USADepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Center of Internal Medicine II, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, GermanyGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USADepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyGerman Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USADepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyEmerging Infectious Disease Program, Duke-NUS Medical School, SingaporeDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, GermanyBackground & Aims: The role of hepatocytes in producing chemokines and triggering liver inflammation and damage in chronic hepatitis D (CHD) is not fully understood. Herein, we investigated the contribution of primary human hepatocytes (PHHs) infected with HDV in triggering inflammation by producing the chemokines CXCL9–11. Methods: We performed quantitative PCR, RNA in situ hybridisation, activation-induced marker (AIM) assays, and FACS analysis to investigate the CXCR3/CXCL9–11 receptor/ligand axis of T cells in peripheral blood and livers from patients with chronic hepatitis B (n = 27 and 18, respectively) and CHD (n = 20 and 18, respectively). Chemokine expression was investigated in cultured HDV-infected PHHs and in livers of HBV- or HBV/HDV-infected humanised mice in the presence or absence of adoptively transferred human immune cells (n = 35 in total). Results: In patient and chimeric mouse livers, higher expression levels of CXCL9–11 were found in an HBV/HDV-coinfected vs. HBV-mono-infected setting. Similarly, high levels of CXCL9–11 were observed in HDV-infected PHHs in vitro. Analysis by RNA in situ hybridisation on patient livers revealed that HDV-infected hepatocytes were a significant contributor to the chemokine expression. The corresponding chemokine receptor CXCR3 was found upregulated specifically on peripheral bulk CD4 T cells of patients with CHD. CXCR3 upregulation was unspecific and was not detected on HDAg- or HBsAg-specific CD4 T cells by activation-induced marker assay. Lastly, adoptive transfer of human T cells in humanised mice led to recruitment of non-HBV/HDV-specific CD4+ T cells only in the setting of HBV/HDV coinfection, but not in HBV-mono-infected mice. Conclusions: HDV infection upregulated the intrahepatic expression of the CXCL9–11/CXCR3 receptor/ligand axis. Higher amounts of HBV/HDV-unspecific CD4 T cells expressing CXCR3 may contribute to the aggravated liver inflammation frequently observed in patients with CHD. Impact and implications: Chronic hepatitis D (CHD) causes the most severe form of viral hepatitis, and treatment options are still limited; therefore, a more precise understanding of CHD immunopathology is needed. In this study, we demonstrated that HDV infection triggers CXCL9–11 expression in hepatocytes and liver infiltration of CXCR3-expressing CD4 T cells in preclinical models as well as patient biopsies. Because recruitment of Th1-polarised CD4 T cells to the liver has been also described for other severe liver diseases, such as autoimmune hepatitis, it may represent an important mechanism of aggravating liver diseases. The data of this study set hereby the basis for future studies analysing phenotype and function of intrahepatic T cells in CHD.http://www.sciencedirect.com/science/article/pii/S2589555924002775HBVHDVCXCL10CXCL9CXCR3Chemokines
spellingShingle Jan-Hendrik Bockmann
Lena Allweiss
Annika Volmari
David da Fonseca Araújo
Matin Kohsar
Anastasia Hyrina
Janine Kah
Zhijuan Song
Josolyn Chan
Katja Giersch
Tassilo Volz
Marc Lütgehetmann
Jeffrey J. Wallin
Dmitry Manuilov
Meghan M. Holdorf
Simon P. Fletcher
Ansgar W. Lohse
Antonio Bertoletti
Julian Schulze zur Wiesch
Maura Dandri
Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
JHEP Reports
HBV
HDV
CXCL10
CXCL9
CXCR3
Chemokines
title Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
title_full Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
title_fullStr Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
title_full_unstemmed Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
title_short Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells
title_sort hepatitis d virus infection triggers cxcl9 11 upregulation in hepatocytes and liver infiltration of cxcr3 cd4 t cells
topic HBV
HDV
CXCL10
CXCL9
CXCR3
Chemokines
url http://www.sciencedirect.com/science/article/pii/S2589555924002775
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