Project Details

Host-Viral Interactions in the Development in Very Early Onset Inflammatory Bowel Disease

Evida Dennis-Heyward, MD, PhD

Summary

BACKGROUND: The cause of inflammatory bowel disease (IBD) is not completely understood but is thought to involve abnormal immune responses to an environmental trigger in individuals with increased genetic risk. Very early onset IBD (VEOIBD) are severe forms of IBD that have a higher likelihood of an underlying single gene mutation. Over 100 VEOIBD gene mutations involved in immune responses, epithelial function, and in regulation of viral infection have been discovered, yet it is not known whether viruses are an environmental trigger of IBD in these patients. GAP: This project aims to address the paradigm of whether viruses are innocent bystanders or contribute to the development of IBD in individuals with increased genetic risk. HYPOTHESIS: My hypothesis is that certain gene mutations predispose to abnormal intestinal immune activation after a viral infection that contributes to the development of IBD. METHODS: I will (1) analyze single cell RNA sequencing data from intestinal biopsies of 170 VEOIBD and 43 non-IBD patients using a Kraken2-based computational pipeline to detect and quantify viruses; (2) analyze serum samples of 69 VEOIBD and 69 non-IBD patients for detection of antiviral antibodies; and (3) directly assess host antiviral immune responses to intestinal viral exposure using patient-derived intestinal organoids from 80 VEOIBD patients and 20 non-IBD patients. RESULTS: Pending. IMPACT: Currently, there is little data to guide optimal management of VEOIBD and treatment options are very limited due to limited understanding of disease pathophysiology. The proposed work will identify VEOIBD gene mutations that increase susceptibility to an abnormal immune response after viral infection, enable the development of assays to investigate patient-specific disease pathogenesis that may inform broader disease mechanisms, and reveal targetable candidates that guide development of alternate therapies.