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.
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.
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.