Élodie Beaumont1, Vincent Larochette2, Laurence Preisser2, Charline Miot3, Pascale Pignon2, Simon Blanchard3, Björn-Thore Hansen4, Jonathan Dauvé5, Caroline Poli3, Minna M Poranen6, Patricia Lamourette7, Marc Plaisance7, Alain Morel8, Helmut Fickenscher4, Pascale Jeannin3, Philippe Roingeard9, Yves Delneste3. 1. INSERM Unit 1259 MAVIVH, University of Tours, Tours, France. Electronic address: elodie.beaumont@univ-tours.fr. 2. Univ Angers, Nantes Université, CHU Angers, INSERM, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France. 3. Univ Angers, Nantes Université, CHU Angers, INSERM, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France; Laboratory of Immunology and Allergology, University Hospital of Angers, Angers, France. 4. Institute for Infection Medicine, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany. 5. ICO Cancer Center, Angers, France. 6. Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. 7. Service de Pharmacologie et d'immunoanalyse, Commissariat à l'Energie Atomique Saclay, iBiTec-S, Gif sur Yvette, France. 8. Univ Angers, Nantes Université, CHU Angers, INSERM, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France; ICO Cancer Center, Angers, France. 9. INSERM Unit 1259 MAVIVH, University of Tours, Tours, France.
Abstract
BACKGROUND & AIMS: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. METHODS: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. RESULTS: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. CONCLUSIONS: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. LAY SUMMARY: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.
BACKGROUND & AIMS: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. METHODS: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. RESULTS: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. CONCLUSIONS: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. LAY SUMMARY: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.