In Inflammatory Bowel Disease (EBV) Epstein-Barr virus (EBV) infection is thought to contribute to disease severity and resistance to therapy. Recently, we discovered a powerful association between the DNA immunoprecipitated by EBNA2 and the risk loci of IBD, intersecting 38 of 112 evaluated loci (from the GWAS catalog in 2015) (RR=3.3, Pc=1.24x10-13) (1). Newer data confirm the EBNA2 association and also show that EBNA3C and EBNALP ChIP-seq (chromatin immunoprecipitation with next generation sequencing) data are also associated with IBD loci (RR=2.3, Pc=2.3x10-12 & RR=2.3, Pc=2.3x10-12, respectively) while BZLF1 (ZTA), an EBV Lytic program transcription factor (TF), is not associated. EBNA2, EBNA3C, and EBNALP are expressed in the EBV Latency III program of viral gene expression, causing the infected B cell to transform and becoming a major target for incomplete destruction by the normal human immune system. Interestingly, human transcription factors (TFs) tend to bind the same loci that are bound by these Latency III EBV gene products, forming intersection clusters that identify the contributing, presumably, regulatory IBD loci. Our interpretation is that these associations strongly suggest that at the intersecting loci viral mechanisms commandeering the cellular phenotype are shared with the genetic mechanisms of IBD risk. We conclude that this relationship likely represents related molecular pathways. The question is whether these associations are correlations, reflecting converging but independent mechanisms, or whether these correlations are interdependent and exist because the virus is etiologic and involved in disease pathogenesis. Establishing either possibility would be a major advance for IBD with viral constituents being probes to dissect mechanism. If EBV infection is etiologic, then, perhaps, the initial EBV-related lesion interferes with the barrier function, allowing the endogenous microbiome to induce the inflammatory response that we recognize as one or more of the pathologies of IBD. Since other EBNA2 associated disorders are autoimmune (1) and some EBV associations with IBD severity are colonic, if EBV is etiologic, then the autoimmunity of Ulcerative Colitis (UC) would be a most likely suspect. We propose to:
Aim 1.) Exploit the discovery of additional IBD risk loci; improvements in our informatics, including allele specific analysis; and the new chromatin immunoprecipitation data accumulated to redefine the associations previously discovered (1).
Aim 2.) Better understand the genomic mechanisms of IBD by applying state-of-the-art genomic technologies.
Aim 3.) Develop new therapeutics for IBD directed against EBV, particularly against the Latency III transforming expression program of EBV, and Aim 4.) Test the prediction of the etiologic possibility that EBV-infection is increased in IBD and, if so, then identify the characteristics of the IBD subset whose illness is related to the inflammatory pathology of IBD, perhaps those with autoimmune UC. This project will determine whether EBV is a plausible etiology for some IBD, characterize regulatory genomic mechanisms in risk loci, and initiate experiments to find new therapies to reduce the impact of EBV on IBD.
Epstein-Barr virus (EBV) infection is thought to push patients with inflammatory bowel disease (IBD) toward more serious disease manifestations and to render them less responsive to the available therapies. Genomics provides a completely new perspective from which to consider EBV in IBD and, surprisingly, the results are consistent with the possibility that EBV works with the risk genes to cause IBD. We will determine whether EBV is likely to cause IBD, develop our genomic findings using better informatics and new data, explore the genomic mechanisms that cause IBD, and develop new anti-EBV therapies to improve IBD by reducing the impact of EBV.
