Molecular analysis of hepatitis C virus - dendritic cell interaction
Zusammenfassung der Projektergebnisse
Hepatitis C virus (HCV) is a major cause of chronic liver inflammation worldwide and the leading indication for liver transplantation. Therapy for HCV-related chronic hepatitis is limited and a vaccine preventing HCV infection is not available. Immunological studies in humans and chimpanzee have shown that T cell immunity can reduce viremia during acute HCV infection and prevent progression to chronic infection. Thus, the induction of prophylactic anti-HCV specific T cell response may help to clear viremia. Dendritic cells (DCs) play a central role in the initiation and regulation of anti-viral immune responses. However, the molecular mechanisms by which DCs initiate HCV-specific T cell response as well as the immunological determinants mediating protective immunity are not completely understood. In this study we investigated the molecular mechanism of HCV antigen uptake and processing by myeloid and plasmacytoid DCs (mDCs and pDCs). Our data implicate a model of HCV antigen processing and presentation in which mDCs and pDCs perform different functions in HCV-specific CD4+ and CD8+ T cell stimulation. The distinct HCV antigen processing pathways may ensure the simultaneous initiation of a rapid and effective HCV-specific CD4+ and CD8+ T cell response. Furthermore, we determined the immunological correlates associated with protective immunity against HCV infection in the chimpanzee model. An extensive analysis of the innate and adaptive immune responses following homologous and heterologous HCV rechallenges in chimpanzees revealed that protective immunity against HCV re-infection is orchestrated by a complex network of innate and adaptive immune responses. Miscueing of this coordinated immune response in the liver leads to failure of viral control and persistent viral infection. In conclusion, we provided novel insights into the molecular mechanism of HCV antigen presentation and determined the immunological correlates associated with protective immunity. Our findings have important implication for our understanding of immunity against HCV and will pave the way for the design of novel prophylactic and therapeutic vaccine approaches against HCV infection.
Projektbezogene Publikationen (Auswahl)
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Early induction of lndoleamine-2,3-dioxygenase in human hepatocytes and dendritic cells may facilitate hepatitis C virus persistence. 16th International Symposium on Hepatitis C Virus and Related Viruses, 3.-7. October 2009, Nice, France
Barth H., Lambotin, M., Huang, Y., T.F. Baumert, T.J. Liang
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Uptake and trafficking of cell culture-derived hepatitis C virus (HCVcc) in human plasmacytoid dendritic cells. 44th Annual Meeting of the European Association for the Study of the Liver (EASL), 22.-26. April, 2009, Copenhagen, Denmark
Lambotin, M., C. Thumann, E. Robinet, F. Stoll-Keller, T.J. Liang, H. Barth, and T.F. Baumert
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Uptake and trafficking of cell culture-derived hepatitis C virus (HCVcc) in human plasmacytoid dendritic cells. 9ème réunion du Réseau National Hépatites de l'ANRS, 22.-23. January 2009, Paris, France
Lambotin, M., C. Thumann, E. Robinet, F. Stoll-Keller, T.J. Liang, H. Barth, and T.F. Baumert
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Uptake and trafficking of hepatitis C virus in plasmacytoid and myeloid dendritic cells. 16th International Symposium on Hepatitis C Virus and Related Viruses, 3.-7. October 2009, Nice, France
Lambotin, M., T.F. Baumert, H. Barth
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Uptake and trafficking of hepatitis C virus in plasmacytoid and myeloid dendritic cells. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) 30. October - 3. November 2009, Boston, USA
Lambotin, M., T.F. Baumert, H. Barth
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A look behind closed doors: Interaction of persistent viruses with dendritic cells. Nat. Rev. Microbiol. 2010, 8: 350-360
Lambotin M, Raghuraman S, Stoll-Keller F, Baumert TF, Barth H
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Distinct pathways of hepatitis C virus trafficking in myeloid and plasmacytoid dendritic cells. J. Virol. 2010, 84: 8964-8969
Lambotin M, Baumert TF and Barth H
