WHAT LESSONS CAN BE LEARNED FROM ANIMAL-MODEL STUDIES IN VIRAL HEART-DISEASE

Several well-defined coxsackievirus B3 (CVB3)-murine models or inflamm atory heart disease are providing information about mechanisms which c ontribute to myocyte necrosis. Severity of disease induced and mechani sms responsible depend upon unresolved molecular activities of the vir al genome, nonspecific defenses of the mouse at time of infection and immune responses of the mouse at the time of infection. Most important are the capabilities and directed responses of each mouse to infectio n which are determined by age and genetic background of the host. In a ddition to virus-induced contributions to tissue pathology during prim ary infection, persistence of viral genomes for weeks to months in som e strains of mice forecast whether the scute disease will resolve or c ontinue as chronic disease with sustained inflammatory reactions in th e myocardium. Persistent infections can contribute to nascent cardiopa thologic alterations by chronic induction of inflammatory events throu gh expression of viral genes and altered expression of host genes duri ng nonlytic infections. Products of these expressions include viral pr oteins and nonhomeostatic levels of cytokines and archidonic acid casc ade intermediates and final metabolites. Molecular mimicry via shared epitopes between virion capsid proteins and normal cell molecules/stru ctures located on or within heart tissue cells may be the mechanism by which immune systems in certain strains of mice are persistently stim ulated.The products of these immune responses, i.e. antibodies and cyt otoxic T lymphocytes, may provide initial protection via termination o f infection and virus clearance during acute disease but subsequently these autoreactive processes could contribute to chronic disease. The immune effector products (antibodies and T lymphocytes) have potential pro-inflammatory reactivities, capacity for exacerbating ongoing CVB3 -induced disease and/or can induce disease in normal animals. In furth er support of the hypothesis that autoimmune reactions contribute to s ustained inflammation of the heart, non-viral models of myocarditis ha ve been developed. Cell constituents such as myosin and adenosine nucl eotide translocator protein can induce cardiopathologic alterations in normal mice of strains known to develop CVB3-induced chronic disease. Thus host genetic background determines whether a mouse survives the initial infection, resolves the acute disease or inadvertently contrib utes to sustained inflammatory heart disease. Finally, shared epitopes among the enteroviruses may play a role in repeated episodes of disea se during sequential infections by different serotypes.