The development of Ulcerative Colitis (UC) is commonly believed to be the result of changes in the balance between the host immune system and gut microbiome. This imbalance can be the result of genetic changes – particularly in immune signaling and regulatory pathways, but these only account for a fraction of the risk, suggesting there are environmental or acquired factors which contribute. Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus which infects billions of people worldwide, but typically without overt pathology. However, CMV infection has a massive impact on the host immune system leading to exaggerated immune responses typified by T cell memory “inflation”, and changing the immune composition and fucntions of blood and organs. This is as a result of continuous stochastic reactivation events in the tissues which it infects - including the colon. Although clinical reactivation of CMV following immune suppression has been well recognised in UC, the longer term subclinical impacts of CMV on UC risk and phenotype have not been explored.
We have addressed this in a preliminary cohort study of nearly 1000 well phenotyped and genotyped patients in Oxford. We find that not only does CMV exposure associate with increased risk of UC diagnosis, but this is particularly linked with patients where the genetic risk is low – in other words CMV appears to act as an additional – and potentially modifiable – risk factor. We aim to test this idea by
a) Performing a detailed independent replication cohort study using well phenotyped and genotyped patients. This will focus particularly on inception cohorts developed at 2 sites and will link CMV status with risk, phenotype, genotype and biomarker status.
b) Perform a detailed cross sectional study of the immunologic milieu of gut tissue in CMV+ vs CMV- healthy donors and UC patients, analyzing innate and immune subsets using FACS, RNASeq and single cell approaches, combined with detailed in situ immune phenotyping by chip cytometry. We will address the frequency, phenotype and function of both myeloid and lymphoid compartments.
c) Define the pathways that link CMV infection and gut inflammation using a murine model of CMV combined with an adoptive transfer model of colitis. This combination will allow dissection of critical immune mechanisms which may be modulated by CMV and which could be addressed in patients.
Overall at the end of this project we aim to firmly establish a statistically robust and clinically relevant link between CMV infection and UC, define human immune signatures which relate CMV infection to UC risk and UC pathogenesis, and provide a mechanistic causative explanation of how this virus may promote UC pathogenesis. This will provide a firm rationale for interventional studies in future which can address this modifiable risk factor for patient benefit.
In vivo models
Immunology & Infectious Disease and Endocrinology & Metabolic Medicine
Project reference number: 951
|Professor Paul Klenerman||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRfirstname.lastname@example.org|
|Dr Carolina Arancibia||Experimental Medicine Division||Oxford University, John Radcliffe Hospital||GBRemail@example.com|
Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8(+) T cells - a phenomenon termed memory inflation - and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits. Hide abstract