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* Department of Medicine II, University of Freiburg, Germany;
Institute of Infectious Diseases, Southwestern Hospital, Third Military Medical University, Chongqing, China;
Faculty of Biology, University of Freiburg, Freiburg, Germany;
Institut National de la Santé et de la Recherche Médicale, U748, Strasbourg, France;
¶ Université Louis Pasteur, Strasbourg, France;
|| Institute for Infection Medicine, Molecular Medical Virology, University of Kiel, Kiel, Germany;
# Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan;
** Institute of Pathology, University of Freiburg, Freiburg, Germany; and
Service d’Hépatogastroentérologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Apoptosis of infected cells represents a key host defense mechanism against viral infections. The impact of apoptosis on the elimination of hepatitis C virus (HCV)-infected cells is poorly understood. The TRAIL has been implicated in the death of liver cells in hepatitis-infected but not in normal liver cells. To determine the impact of TRAIL on apoptosis of virus-infected host cells, we studied TRAIL-induced apoptosis in a tissue culture model system for HCV infection. We demonstrated that HCV infection sensitizes primary human hepatocytes and Huh7.5 hepatoma cells to TRAIL induced apoptosis in a dose- and time-dependent manner. Mapping studies identified the HCV nonstructural proteins as key mediators of sensitization to TRAIL. Using a panel of inhibitors targeting different apoptosis pathways, we demonstrate that sensitization to TRAIL is caspase-9 dependent and mediated in part via the mitochondrial pathway. Sensitization of hepatocytes to TRAIL-induced apoptosis by HCV infection represents a novel antiviral host defense mechanism that may have important implications for the pathogenesis of HCV infection and may contribute to the elimination of virus-infected hepatocytes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the Fritz Thyssen Stiftung (to R.F.), Germany, the Faculty of Medicine, University of Freiburg, Germany (to R.F. and A.S.-G.), and by grants of Institut National de la Santé et de la Recherche Médicale, France, the European Union (LSHM-CT-2004–503359 "VIRGIL"; to T.F.B.), Belgium, the chair of excellence program of the Agence Nationale de la Recherche (ANR-05-CEXC-008; to T.F.B.), France, the Agence Nationale de la Recherche sur le SIDA et les Hépatites Virales (ANRS 06221; to T.F.B.), France, the Deutsche Forschungsgemeinschaft (Ba1417/11–2; to T.F.B.), Germany, France and the Else Kröner-Fresenius Foundation, Bad Homburg, Germany (P17/07//A83/06; T. F. B.). M.B.Z. was supported by the Inserm Poste Vert program in the framework of Institut National de la Santé et de la Recherche Médicale European Associated Laboratory Freiburg-Strasbourg. T.W. is supported by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science, from the Ministry of Health, Labour and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology, and by the Research on Health Sciences Focusing on Drug Innovation from the Japan Health Sciences Foundation.
2 L.L. and S.G. contributed equally to this study.
3 R.F. and T.F.B. contributed equally to this study.
4 Address correspondence and reprint requests to Dr. Richard Fischer, Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. E-mail address: richard.fischer.medizin{at}uniklinik-freiburg.de
5 Abbreviations used in this paper: HCV, hepatitis C virus; PHH, primary human hepatocyte; MOI, multiplicity of infection; JFH1, Japanese fulminant hepatitis 1 isolate; HCVcc, cell culture-derived HCV; PARP, poly (ADP-ribose) polymerase; HBV, hepatitis B virus.
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