The etiopathogenesis of Theiler's murine encephalomyelitis virus (TMEV)- induced cardiomyopathy, including characterization of new strains of TMEV

Abstract

Strains of the picornavirus, Theiler's murine e ncephalomyelitis virus (TMEV), are subgrouped by neuroviruience, with the GDVII-subgroup strains inducing an acute fatal polioencephatitis, and the TO subgroup strains being associated with viral persistence and chronic demyelinating disease. Although well recognized for their poliovirus-like biologic behavior, the TMEV were recently reclassified as cardioviruses due to genetic homology with this genus. In spite of rare reports of TMEV isolation from heart tissues, TMEV has never been associated with the development of a cardiomyopathy. This report demonstrates cardiotropism for a virulent strain of TMEV, GDVII, and a new strain, Tex, and associates myocardial infection with acute myofiber lesions and a chronic degenerative cardiomyopathy. Tex-induced myocardial lesions were found to differ among three strains of mice, suggesting host strain-related differences in primary mechanisms of pathogenesis. Two GDVII-like viruses were isolated from the DA-derived Tex strain. These isolates, tex-s and tex-1, possess GDVII epitopes while lacking DA epitopes in the VPl viral capsid protein. In addition, these isolates lack DA-specific sequences in the VPl coding region and lack a DA-specific restriction endonuclease site in the VP2 coding region. Rather, these isolates both posses GDVII-like sequences and a GDVII-specific restriction site in the VP2 coding region. However, tex-s is markedly more neurovirulent than tex-1, resembling the GDVII-subgroup in histopathology and clinical disease, while tex-I infections resemble the TO-subgroup and are associated with a chronic cardiomyopathy. Coinfections of tex-I and tex-s result in attenuation of tex-s neurovirulence, indicating interference between these two strains. Though viral interference can be mediated by interferon, no significant differences were detected between the tex-s and tex-I strains in interferon sensitivity, and both were strong inducers of the antiviral effect. In comparison, the DA strain was relatively interferon resistant and demonstrated a minimal propensity to induce the anti- viral effect while the GDVII strain, though similar to both tex-s and tex-I in sensitivity to interferon, appeared to inhibit the induction of the antiviral effect under identical conditions. A theoretical model of interstrain interference and pathogenesis of TMEVinduced cardiomyopathy is proposed.