Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner
Fiche publication
Date publication
octobre 2008
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas
Tous les auteurs :
Lan L, Gorke S, Rau SJ, Zeisel MB, Hildt E, Himmelsbach K, Carvajal-Yepes M, Huber R, Wakita T, Schmitt-Graeff A, Royer C, Blum HE, Fischer R, Baumert TF
Lien Pubmed
Résumé
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.
Référence
J Immunol. 2008 Oct 1;181(7):4926-35.