P057 Caudovirales may trigger molecular mimicry mechanisms in Crohn’s Disease

Abstract

Abstract Background The gut virome is known to play a role in the development of Crohn's disease (CD), a type of Inflammatory Bowel Disease (IBD). Several years ago, Norman and colleagues observed an expansion of Caudovirales linked to CD pathogenesis, alongside a reduction in bacterial diversity. To delve deeper, we exploited the IBD TaMMA framework and observed a significantly higher abundance of Caudovirales in the CD individuals compared to healthy controls, confirming earlier findings. Methods To further examine the involvement of this viral species in various mucosal cell compartments, we conducted flow cytometry cell sorting (FACS) on intestinal biopsies from CD and healthy individuals. Isolated immune and non-immune cells based on population-specific markers, including CD8 and CD4 T cells, B cells, macrophages, dendritic cells, epithelium, endothelium, and fibroblasts underwent transcriptomics and metatranscriptomics. Results We identified higher abundance of the Proteus virus Isfahan, belonging to Caudovirales viral order, in CD dendritic cells and CD macrophages compared to their healthy counterparts. Notably, gene ontology (GO) analysis indicated that only CD dendritic cells, fibroblasts, and epithelial cells exhibited compromised biological responses to viral insults compared to their healthy counterparts. In contrast, CD macrophages displayed upregulation of molecular pathways regulating viral processes. This suggests that virome dysbiosis in these cells may contribute to CD pathogenesis by altering their biological functions. We thus wondered whether Proteus virus Isfahan encoded proteins had similarities with the human ones, somehow establishing molecular mimicry justifying the likelihood of the autoimmune nature of CD. We observed sequence homology in the Proteus virus Isfahan and the human thymidylate synthase, RECQ-like DNA helicase, and dCMP deaminase. These viral proteins are likely to be recognized by the immune system by sharing similarities with the human homologs, thus activating autoreactive immune response and establishing the persistent chronic inflammatory environment within CD mucosa. Experiments employing T helper cells in coculture with Proteus virus Isfahan proteins-overexpressing innate immune cells are ongoing to prove the autoreactive activation of the host’s immunity. Conclusion Given the growing evidence of viral entities as triggers for IBD, these data could pave the way for discovering viruses directly involved in CD pathogenesis and serving as the booster for molecular mimicry mechanisms, finally providing potential targets for novel intervention strategies that may improve CD management.