• Chantler, Janet

    Titles

    Investigator Emerita, BC Children's Hospital
    Professor, Department of Pathology, University of British Columbia

    Degrees / Designations
    B.Sc.(Hons), PhD
    Primary Area of Research
    Secondary Area(s) of Research
    Phone
    604-875-3262
    Fax
    604-875-3674
    Lab Phone
    604-875-3674
    Assistant
    Xiaoxie Wang
    Mailing Address

    BC Children's Hospital Research Institute
    Room A4-198 WS
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas

    The pathogenesis of coxsackieviruses, including their role in diabetes and heart disease

    Summary

    The coxsackieviruses are ubiquitous viruses that cause many of the common summer "flu-like " diseases. There are 23 group A and six group B coxsackieviruses; we are infected by many different strains over our lifespan. Most of these infections manifest as only a mild fever, muscle aches and, sometimes, a rash, but there is mounting evidence that these viruses are more pathogenic than previously thought. For example, coxsackieviruses can cause aseptic meningitis in very young children, and there is evidence that they cause chronic heart damage in some patients by infecting and damaging cardiomyocytes - the muscle cells of the heart. Certain group B coxsackieviruses are also believed to trigger type 1 diabetes in genetically susceptible children. Our research is directed at understanding the underlying mechanisms by which these viruses cause long-term complications, with a view to developing novel treatment strategies as well as a combined attenuated vaccine that would protect against the most virulent serotypes.

    Current Projects

    Association of group B coxsackieviruses with type 1 diabetes
    There has been mounting evidence that the Group B coxsackieviruses (CVB) can trigger type 1 diabetes. The most definitive evidence is the recent finding of the viral genome in serum of 40-60% of recently diagnosed patients. At present, however, there is limited and, in some cases, contradictory information on how these viruses cause insulin deficiency. Some CVB strains are believed to infect cells in the islets of Langerhans more efficiently than other strains, and this has been proposed to cause direct killing of beta cells, the cells that produce insulin. Another proposed mechanism is that the virus triggers an inflammatory immune reaction, including the production of cytokines or activated T-cells that can cause "collateral" damage to nearby islet cells.

    In our studies, we have used a well-established murine model system (SJL mice) to compare the pathological events that occur in the pancreas following infection with a "diabetogenic" variant of CVB4 (the E2 strain) with the "non-diabetogenic" JVB prototype strain. This study has lead us to propose a further mechanism underlying CVB-induced diabetes that involves viral damage to the exocrine tissue and lack of islet neogenesis in causing beta cell depletion. We are currently investigating the process of pancreatic regeneration that occurs following infection of SJL mice with the JVB non-diabetogenic strain. This includes characterization of the cytokines and growth factors produced in the tissue that stimulate regeneration of both acinar and islet cells. We hope that this research will lead to novel therapies for type 1 diabetes, based on stimulation of the patient's own progenitor cells to regenerate islet tissue or, if this is not possible, to enhance the ability of transplanted islets to reconstitute the islet mass.

    Cardiovirulence of Group B Coxsackieviruses
    In addition to their role as possible triggers of type 1 diabetes, the group B coxsackieviruses are also thought to be etiological agents of human myocarditis. Many viruses have been shown to be capable of damaging the heart but the coxsackieviruses are the ones most frequently involved. Recent evidence identifying the viral genome in cases of acute myocarditis have indicated that these viruses are associated with as high as 25-50% of cases.

    An understanding of the molecular basis of cardiovirulence of these viruses is therefore of paramount importance in reducing the toll of human heart disease. While the number of coxsackievirus serotypes has discouraged attempts to produce a vaccine, even protection against the most cardiovirulent strains (CVB3,4 and 5) could significantly reduce the morbidity associated with these infections. The proposed study is aimed at constructing a highly attenuated CVB3 strain that could provide the basis for a CVB3 vaccine. In addition, investigation of the underlying mechanism of cardiovirulence may point to new treatment strategies to limit damage to heart tissue by these viruses.

    Selected Publications

    Sadeghi A, Stadnick E., Chantler JK. Properties of an amyocarditic variant of CVB3 (manuscript submitted, February 2003)

    Robbins, M. Pocock, E. and Chantler, J.K. NFkB nuclear translocation is required for caspase dependent death of beta cells treated with dsRNA. (manuscript submitted to Endocrinology, February, 2003.

    Yap, I. Giddings, G. and Chantler, J.K. Lack of islet neogenesis plays a key role in beta cell depletion in mice infected with a diabetogenic variant of coxsackievirus B4. (manuscript submitted, January, 2003)

    Kavoosi M, Sadeghi A, Girn J and Chantler JK. Enhancement of Coxsackievirus B3 infection of macrophages by antibody to a different coxsackievirus strain. J Gen Virology, 83 351-358, 2002

    Chantler JK, Wolinsky JS and Tingle AJ. Rubella virus. In: Field's Virology, Eds DM Knipe and PM Howley. Published by Grune and Stratton, June 2001

    Lund K, Chantler JK. Mapping of genetic determinants of rubella virus associated with growth in joint tissue. J.Virology 74(2) 796-804, 2000

    Grants
    Honours & Awards
    Research Group Members
    • Meixia Dan - Research associate
    • Marjorie Robbins - Postdoctoral fellow
    • Emma Pocock - Research techninian
    • Michaela White - Graduate student