DOP027 Caudovirales may trigger molecular mimicry mechanisms in Crohn’s Disease
Authors: Errico C , Massimino L , Nicolò S , Spanò S , Facoetti A , Cagliani S , Parigi T L , Bozzetti V , Riva M , Danese S , Ungaro F 
Published: January 2025

Abstract

Background
Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), has been increasingly associated with imbalances in the gut microbiota. Dysregulation within the gut virome has been linked to CD pathogenesis, with elevated levels of Caudovirales observed in CD patients1. Among them, we found the Proteus virus Isfahan species as considerably abundant in CD but absent in UC. We hypothesized that this virus can induce a potential molecular mimicry mechanism, causing a CD’s autoimmune response. This project aims to investigate whether Proteus virus Isfahan proteins exhibit homology with human proteins, potentially triggering an autoimmune response.

Methods
To assess Proteus virus Isfahan's correlation with CD, we utilized the IBD Transcriptome and Metatranscriptome Meta-Analysis (TaMMA) framework2, analyzing immune and non-immune cell populations from intestinal biopsies of CD patients and healthy controls. Cells, including CD4 and CD8 T cells, B cells, macrophages, dendritic cells, fibroblasts, and epithelial cells, were isolated using flow cytometry (FACS) and subjected to transcriptomic analysis. Furthermore, to investigate Proteus virus Isfahan’s role in CD, viral proteins were assessed for homology to human proteins using in silico tools such as NCBI BLAST and iPBA. Additionally, in vitro experiments coculturing T cells with immune cells overexpressing Proteus virus Isfahan proteins are underway to explore immune responses.

Results
Our analyses confirmed increased levels of Caudovirales, especially Proteus virus Isfahan, in cells from CD patients compared to controls, particularly in dendritic cells and macrophages. Gene ontology (GO) analysis indicated compromised responses in dendritic cells, while CD macrophages displayed upregulated viral-response pathways. Viral proteins gp16 and gp82 showed structural homology with human thymidylate synthase and dCMP deaminase, supporting the hypothesis of molecular mimicry. Results highlighted Proteus virus Isfahan as an activator of autoreactive T cells, contributing to CD-associated autoimmunity and disruption of intestinal cells.

Conclusion
These findings suggest that gut virome-associated Proteus virus Isfahan species play a role in CD pathogenesis through molecular mimicry. The viral proteins’ similarity to human proteins could lead to immune misrecognition, triggering autoimmunity and sustaining the inflammatory environment in CD patients. Ongoing experiments aim to validate these interactions and clarify the immune response, potentially identifying Proteus virus Isfahan as a target for novel therapeutic interventions.

References
1. Norman, J.M. et al. "Disease-specific alterations in the enteric virome in inflammatory bowel disease." Cell vol. 160,3 (2015): 447 60.
2. Massimino, L. et al. The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework. Nat Comput Sci 1, (2021):511–515.