Crohn's disease (CD) is a multifactorial and complex disease, orchestrated by several genetic and environmental triggers. The best known genetic marker for CD is the nucleotide oligomerization domain 2 (NOD2), a cytoplasmic receptor that responds to bacterial pathogens. Mutations in NOD2 are the strongest genetic marker for CD and the only proven risk factor for stricturing phenotypes. The fact that mutations in NOD2 result in CD only in some individuals but not in others indicates that environmental factors may contribute to or trigger CD. CMV, a common viral infection, establishes life-long latency in the host including in intestinal epithelial cells. Our laboratory reported that NOD2 suppresses CMV replication, but the NOD2 mutant 3020insC, associated with severe CD, is unable to inhibit CMV replication in vitro. NOD2 activation with muramyl dipeptide (MDP) inhibits CMV replication in vitro. Furthermore, MDP treatment of mouse CMV (MCMV) infected macrophages results in virus suppression. In contrast, in macrophages collected from NOD2-deficient mice MDP cannot suppress virus replication. These data provide strong support for the role of CMV as a modifier of NOD2 innate immune responses and CD pathogenesis. We hypothesize that CMV infection contributes to the natural history and complications of CD, especially in genetically prone individuals who carry NOD2 mutations. We will use the NIDDK IBD Genetics Consortium (IBDGC) tissue bank and corresponding data from their ?Ileal Post-Operative Recurrence Study? of CD patients that have undergone ileal resection for any indication. We will determine whether CMV is more readily detected in tissue samples from patients with NOD2 mutations. Analysis will be controlled for drugs such as steroids and other immunosuppressive agents. In cases of CMV detection in tissue samples we will quantify CMV DNA in blood. The contribution of CMV to stricturing disease behavior and to early post-operative recurrences will also be determined in tissue samples. Our study will provide the first detailed evaluation of CMV as a risk factor for CD stricturing complications in the context of a specific genetic background. Understanding the interplay between genetic and infectious triggers of CD may lead to the development of biomarkers for disease sequalae and inform future therapeutic strategies. Data from our studies could have major clinical implications for patients with CD, as individuals with known NOD2 loss of function mutations may benefit from early diagnosis of CMV, prophylaxis or anti-viral therapy.
Infection with Human Cytomegalovirus (CMV) is common and can cause significant morbidity and mortality in congenitally-infected newborns and immunocompromised hosts. CMV is detected in the intestine in Crohn's disease (CD), but its role as disease modifier and outcome contributor has not been well-studied. Based on our in vitro and in vivo findings of CMV control by NOD2, a genetic marker for CD, we propose investigating the contribution of CMV to the natural history of Crohn's disease, especially in different NOD2 genetic backgrounds.
