Differentiation-associated ISG expression of NK cells in chronic viral infection
Franziska Keller,
Robert Lorenz Chua,
Timo Trefzer,
Katharina Jechow,
Liane Bauersfeld,
Fabian Beier,
Sagar,
Özlem Sogukpinar,
Giuseppe Rusignuolo,
Marta Rizzi,
Roland Eils,
Andreas Pichlmair,
Marco Binder,
Bertram Bengsch,
Christoph Neumann-Haefelin,
Volker Lohmann,
Tobias Boettler,
Christian Conrad,
Robert Thimme,
Maike Hofmann
Affiliations
Franziska Keller
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Baden-Württemberg, Germany
Robert Lorenz Chua
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10178 Berlin, Germany
Timo Trefzer
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10178 Berlin, Germany
Katharina Jechow
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10178 Berlin, Germany
Liane Bauersfeld
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Fabian Beier
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Sagar
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Özlem Sogukpinar
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Giuseppe Rusignuolo
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Marta Rizzi
Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Roland Eils
Faculty of Biology, University of Freiburg, 79104 Freiburg, Baden-Württemberg, Germany
Andreas Pichlmair
Technical University of Munich, School of Medicine, Institute of Virology, 81675 Munich, Bavaria, Germany; German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Bavaria, Germany
Marco Binder
Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (D430), German Cancer Research Center, 69120 Heidelberg, Baden-Württemberg, Germany
Bertram Bengsch
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Christoph Neumann-Haefelin
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Volker Lohmann
Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, University of Heidelberg, Heidelberg, Germany; German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Baden-Württemberg, Germany
Tobias Boettler
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Christian Conrad
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10178 Berlin, Germany
Robert Thimme
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany
Maike Hofmann
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center- University of Freiburg, 79106 Freiburg, Baden-Württemberg, Germany; Corresponding author
Summary: Natural killer (NK) cell responses are modulated by type-I interferons (IFNs) in viral infection. Chronic hepatitis C virus (HCV) infection, marked by robust IFN signatures, shows NK cells with reduced cytokine release but heightened cytotoxicity. Comparable alterations occur in chronic hepatitis B virus (HBV) infection even without a pronounced IFN milieu, implying additional regulatory layers. We analyzed NK cells from healthy donors and patients with chronic HBV or HCV and found conserved expression patterns of interferon-stimulated genes (ISGs) such as IFITM3, IRF1, IFIT2, and ISG20 that correlated with NK cell differentiation state. These genes are governed by fate-determining transcription factors, including ETS1, FLI1, and Eomes, and appear to be constitutively expressed rather than driven by persistent IFN exposure. Network analysis suggested that NK cell ISGs participate not only in antiviral defense but also in processes such as transport and metabolism, underscoring their role in shaping NK responses during health and chronic viral infection.
