Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner.
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.
Lan
Lin
L
Department of Medicine II, University of Freiburg, Germany.
Gorke
Sebastian
S
Rau
Sibylle J
SJ
Zeisel
Mirjam B
MB
Hildt
Eberhard
E
Himmelsbach
Kiyoshi
K
Carvajal-Yepes
Monica
M
Huber
Roman
R
Wakita
Takaji
T
Schmitt-Graeff
Annette
A
Royer
Cathy
C
Blum
Hubert E
HE
Fischer
Richard
R
Baumert
Thomas F
TF
D017209:Apoptosis / Q000276:immunology*; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology; D053453:Caspase 9 / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017353:Gene Deletion; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000235:genetics; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000096:biosynthesis / Q000235:genetics; D015678:Viral Structural Proteins / Q000096:biosynthesis / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D053453:Caspase 9; D053221:TNF-Related Apoptosis-Inducing Ligand; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins; C087035:E1 protein, Hepatitis C virus; C505653:TNFSF10 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase