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Dengue virus replication in human hepatoma cells activates NF-kappaB which in turn induces apoptotic cell death
P Marianneau1, A Cardona, L Edelman
1Unité des Arbovirus et Virus des Fièvres Hémorragiques, Institut Pasteur, Paris, France.
Insights
Dengue virus infection can cause liver injury, leading to apoptosis in liver cells. Nuclear factor-kappa B (NF-kappaB) activation during infection indicates its role in dengue-induced liver cell death.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Dengue hemorrhagic fever-dengue shock syndrome (DHF-DSS) can cause liver injury.
- Councilman bodies in liver biopsies suggest hepatocyte apoptosis in DHF-DSS.
Purpose of the Study:
- To investigate the role of apoptosis in dengue virus-induced liver injury.
- To explore the involvement of NF-kappaB in dengue virus-induced hepatocyte cell death.
Main Methods:
- Infection of HepG2 hepatoma cells with dengue type 1 virus.
- Monitoring of cell death and NF-kappaB activation.
- Treatment of infected cells with NF-kappaB decoys.
Main Results:
- Dengue virus type 1 infection induced apoptosis in HepG2 cells late in the viral cycle.
- NF-kappaB activation occurred concurrently with viral protein synthesis, preceding apoptosis.
- Inhibition of apoptosis was observed upon treatment with NF-kappaB decoys.
Conclusions:
- Hepatocytes infected with dengue virus undergo apoptosis in vitro.
- NF-kappaB plays a critical role in the induction of apoptosis in dengue virus-infected hepatocytes.
- Hepatocyte apoptosis may be a key factor in the pathophysiology of liver failure associated with DHF-DSS.
Abstract:
The severe outcome of the dengue (DEN) virus infection known as DEN hemorrhagic fever-DEN shock syndrome (DHF-DSS) is, in some cases, accompanied by liver injury. Councilman bodies observed in liver biopsies of DHF-DSS cases may correspond to hepatocytes in apoptosis. We show here that infection of the hepatoma cell line HepG2 with DEN type 1 virus induced cell death typical of apoptosis late in the virus cycle. The transcription factor NF-kappaB was activated concomitantly with viral protein synthesis and thus before the appearance of apoptotic cells. Inhibition of apoptosis was observed when DEN virus-infected cells were treated with NF-kappaB decoys, indicating the involvement of this transcription factor in induction of cell death. Thus, infected hepatocytes appear to be subject to apoptosis in vitro, and this may be a key element in the pathophysiology of hepatic failure associated with DHF-DSS.