Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure
Miriam Bittel1, Andreas E Kremer1, Michael Stürzl2
1Department of Medicine 1, University hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Abstract:
During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi's sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.
Insights
Viral FLIP (vFLIP) protein expression in mice livers caused severe injury, inflammation, and early death by inducing necroptosis. This highlights viral proteins
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Viruses produce proteins, such as viral FLIP (vFLIP) from Kaposi's sarcoma-associated herpesvirus, that disrupt host cell death pathways.
- vFLIP specifically inhibits Caspase-8, a key enzyme in initiating apoptosis.
Purpose of the Study:
- To investigate the in vivo effects of anti-apoptotic viral proteins, specifically vFLIP, on liver physiology.
- To analyze the molecular mechanisms underlying vFLIP-induced liver pathology.
Main Methods:
- Generation of transgenic mice with constitutive hepatocyte expression of vFLIP (vFlipAlbCre+).
- Assessment of liver tissue injury, hepatocellular death, inflammation, and survival rates.
- Molecular analysis of cell death pathways, including TNF signaling and necroptosis mediators (RIPK1-MLKL).
Main Results:
- Constitutive vFLIP expression in hepatocytes led to severe liver injury, massive hepatocellular necrosis, and inflammation.
- Mice exhibited early postnatal death, with hepatocellular death mediated by RIPK1-MLKL necroptosis driven by autocrine TNF.
- Impaired bile acid production and bile duct structure disruption were observed, impacting the liver-gut axis.
Conclusions:
- Transgenic vFLIP expression induces severe liver injury and multiple organ dysfunction in mice, ultimately leading to death.
- Viral cell death regulatory molecules possess functions beyond apoptosis inhibition, necessitating comprehensive in vitro and in vivo studies.
- vFLIP's impact on liver homeostasis and the liver-gut axis underscores the complex interplay between viral factors and host physiology.
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