Lay Summary
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
We study retroviral induction of autoimmune and idiopathic inflammatory gastrointestinal and liver disorders. We have characterized a retrovirus in patients with primary biliary cirrhosis and are presently studying the possibility that a viral infection is associated with inflammatory bowel disease and the related liver diseases primary sclerosing cholangitis and autoimmune hepatitis. For example, we have been looking for markers in subjects suffering from primary sclerosing cholangitis, autoimmune hepatitis as well as inflammatory bowel disease in order to find evidence of viral infection. These studies are potentially important, as we do not know whether viruses play a role in damaging the intestine in patients with inflammatory bowel disease. If they do, these agents may trigger a cascade of events that leads to a loss of tolerance to bacteria in the gut and inflammation, which in turn perpetuates chronic disease.
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.
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
We study retroviral induction of autoimmune and idiopathic inflammatory gastrointestinal and liver disorders. We have characterized a retrovirus in patients with primary biliary cirrhosis and are presently studying the possibility that a viral infection is associated with inflammatory bowel disease and the related liver diseases primary sclerosing cholangitis and autoimmune hepatitis. For example, we have been looking for markers in subjects suffering from primary sclerosing cholangitis, autoimmune hepatitis as well as inflammatory bowel disease in order to find evidence of viral infection. These studies are potentially important, as we do not know whether viruses play a role in damaging the intestine in patients with inflammatory bowel disease. If they do, these agents may trigger a cascade of events that leads to a loss of tolerance to bacteria in the gut and inflammation, which in turn perpetuates chronic disease.
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.