Scientific Abstract
Proposal No. IBD-0270
Principal Investigator: Andrew L. Mason, MBBS
Applicant Organization: University of Alberta (Edmonton, Canada)
Project Title: Viral triggers of inflammatory bowel disease
Period of Award: May 1, 2009 – April 30, 2011
Hypothesis: Patients with and inflammatory bowel disease (IBD) and the related liver disorders primary sclerosing cholangitis (PSC) and autoimmune hepatitis have evidence of a complicated infection that includes both a viral and bacterial components. There are several lines of evidence to suggest that these diseases occur as a result of an infectious process in susceptible individuals. For example, the diseases cluster in families and specific geographic locations. Moreover, liver transplant recipients with PSC have a much higher chance of developing recurrent disease with biliary strictures if they have not had a colectomy prior, suggesting that the intact colon is a potential reservoir for infectious agents.
Preliminary studies: The data suggestive of viral infection in patients with IBD and PSC was originally uncovered during studies investigating a retroviral etiology of primary biliary cirrhosis. We found that a proportion of patients with IBD, PSC and autoimmune hepatitis had antibody reactivity with several retroviruses including HIV, HTLV-1 and murine leukemia virus (MuLV). Using a commercial reverse transcriptase (RT) assay, we also found that a high proportion of patients with IBD, PSC and autoimmune hepatitis had RT activity in plasma.
As part of our viral discovery program, we have identified and cloned viruses from patients with primary biliary cirrhosis, PSC, autoimmune hepatitis and IBD. We have also established a co-cultivation assay to assess viral infectivity by culturing homogenized lymph nodes derived at the time of surgery with normal biliary epithelial cells or used virus extracted from bile with HeLa cells and other permissive cell lines. Our best characterized agent is a novel human betaretrovirus derived from patients with primary biliary cirrhosis. We have linked this agent with disease by demonstrating that the virus produces a disease specific phenotype in vivo and in vitro. Moreover, we have shown that patients develop significant histological, biochemical and clinical responses to combination antiviral therapy. Recently, we have found that a highly related virus causes a similar disease in a mouse model of primary biliary cirrhosis and are using this model to identify novel therapeutic regimens to treat patients with primary biliary cirrhosis.
A major problem with viral discovery in humans is that viruses are plentiful, easily discovered, and some only cause disease on a specific background. Because of this, full-length viral sequence is often needed to distinguish pathogenic MuLV-like viruses in humans from potentially defective or non-pathogenic agents.
Research Plan: Due to the detection of multiple retroviral and other viral agents in patients with IBD and liver disease, we have broadened our investigations to metagenomics. A major advantage of metagenomics is that the process is unbiased, relatively insensitive to low copy number, lacks the inherent problem of other techniques, such as polymerase chain reaction that can be contaminated. Moreover, these studies have the potential to provide a complete representation of all viruses and other microbes within the environment. Our goal is to help distinguish potential pathogens from common agents that cause no apparent harm. To achieve these goals, we have initiated collaboration with the Beijing Institute of Genomics and are currently using second generation Illumina/Solexa and 454 pyrosequencing help provide a more complete representation of viruses and other microbes within the gut and related body compartments. By studying IBD and control patients to obtain viral sequence data of available species, we plan to investigate whether viruses play an important role in IBD.