Impact of Virus-Induced Autophagy on Intestinal Immunity

In Austria, approximately 80.000 individuals are diagnosed with Crohn`s disease or ulcerative colitis, conditions collectively termed inflammatory bowel disease (IBD). IBD is currently incurable. It is believed that an aberrant immune response to the intestinal microflora causes the disease, but the exact etiology remains elusive. Genetic studies point towards a role for autophagy and antiviral innate immunity for the development of IBD. Yet, the mechanistic link between these two processes and their modes of operation in the intestinal epithelium are largely unknown. Innate immunity is the first line of defense against invading pathogens and is accomplished through the action of several pattern recognition receptors. The family of RIG-I-like receptors sense viral RNA in the cytosol of infected cells, whereas the Toll-like receptors 3, 7/8 and 9 monitor the extracellular space for viruses. Virus detection by these receptors activates a signaling cascade that leads to induction of type I interferon and interferon-stimulated genes. These defense factors establish an antiviral state in the infected and adjacent cells. Several interferon- stimulated genes act by inducing autophagy. This process is characterized by the formation of double membrane- bound vesicles called autophagosomes that sequester specific portions of cytosol, entire organelles or pathogens. Once sequestered, the autophagosomal components are delivered to lysosomes and degraded. The proposed project is based upon the hypothesis that viral infections sensed by the receptors of the innate immune system induce autophagy in the intestinal epithelium. Conversely, I speculate that in absence of autophagy, viral infections compromise the epithelial barrier function and as a consequence cause an inflammatory response to the commensal flora of the intestine. This hypothesis is strongly supported by murine models in which the animals develop an IBD-phenotype only if a genetic deficiency of autophagy and a persistent viral infection coincide. The following aims outline how I will test this hypothesis: 1. To define which virus-induced innate immune responses trigger autophagy in intestinal epithelial cells. 2. To determine if autophagy represents an antiviral mechanism in intestinal epithelial cells. 3. To determine if viral infection sensitizes intestinal epithelial cells to bacterial stimuli. In summary this study will characterize comprehensively the virus-induced innate immune reponse in the intestinal epithelium and the crosstalk between antiviral immunity and autophagy in order to further our knowledge on the etiology of IBD.