Viral infection sensitizes hepatocytes towards TNF-induced apoptosis

We identified a novel mechanism by which CD8 T cells selectively eliminate virus-infected hepatocytes without direct MHC class I recognition. This mechanism involves TNF secreted by CD8 T cells, which selectively induces death of infected hepatocytes. Triggering of the TNF receptor can induce both, pro-survival pathways via NFkB activation, and apoptotic pathways involving generation of ROS and caspase activation. The molecular mechanisms directing into one or the other pathway are still unknown. However, in virus-infected hepatocytes stimulation of the TNF receptor induces apoptotic pathways, whereas uninfected hepatocytes survive. Here, we investigate the molecular mechanism(s) underlying the sensitization of infected hepatocytes towards the apoptosis-inducing effect of TNF.

In our working model mice infected with a hepatotropic adenovirus are challenged with recombinant TNF. Using biochemical and histochemical analyses we demonstrate that viral infection overcomes different checkpoints regulating TNF apoptosis signaling: Viral infection influences TNF signaling at very early stages, triggering an activation of the initiator caspase 8 and a NOX-dependent induction of ROS, but preventing TNF induced translocation of the NFkB subunit p65/RelA to the nucleus. Furthermore, augmented mitochondrial vulnerability with elevated cytoplasmatic levels of mitochondrial pro-apoptotic proteins upon viral infection contributes to sensitization of hepatocytes towards apoptosis. Ultimately, viral infection led to a down regulation of the x chromosome linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspase 3, and thereby enabling full effector caspase activity for execution of apoptosis.

Taken together, our results have identified a novel immune effector mechanism against virus-infected cells that acts independent of direct MHC class I recognition but whose selectivity is based on effects of viral infection on molecular clues of TNF signaling pathways.

TNF signaling - apoptosis - viral infection