A single viral caspase-8 inhibitor is able to disrupt intestinal immune homeostasis in vivo

Recently it could be demonstrated that mice lacking caspase-8 expression in intestinal epithelial cells (IECs, Casp8^ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and showed a high amount of Paneth cell death, indicating dysregulated antimicrobial immune cell functions in IECs (Nature, 2012). The caspase-8 activity can be tightly regulated by cellular FLIPs (cFLIPs). Interestingly certain viruses express a viral FLIP (vFLIP) which shares structural similarities with cFLIP. To elucidate the ability of vFLIP to influence the caspase-8 activity and the gut homeostasis, we analyzed mice, which express vFLIP only in IECs. These mice showed spontaneous development of inflammatory lesions and a high amount of immune cell infiltration, underlined by increased expression of proinflammatory markers. Moreover they showed a reduction in Paneth cell number and a high amount of cell death in the small intestine. Furthermore we could discover a dysregulation of the NFκB pathway in the intestinal epithelium. Taken together, they show a dramatic phenotype which shares similarities with the phenotype of  Casp8^ΔIEC mice, indicating a dysregulation in the immune defence. The observation of the high amount of cell death suggests that vFLIP might control the caspase-8 activity and therefore interact with the cell death protein platform.