Systemic inflammatory and metabolic disease progression persists despite prevention of myocarditis in Isg15-deficient Coxsackievirus B3 infection.

摘要

INTRODUCTION: Type I interferon responses are critical determinants of organ-specific antiviral control and metabolic adaptation during Coxsackievirus B3 (CVB3) infection. The interferon-stimulated gene ISG15 integrates antiviral defense with immunometabolic adaptation, and its deficiency aggravates viral myocarditis, systemic inflammation, metabolic wasting, and impaired cardiac performance. Previous studies further demonstrated impaired cardiac energetic adaptation in Isg15-deficient mice during CVB3 infection, raising the possibility that aggravated myocardial infection contributes to infection-associated wasting and systemic disease progression. We therefore investigated whether selective prevention of myocardial viral replication attenuates systemic inflammatory and metabolic deterioration during CVB3 infection in Isg15-deficient mice. METHODS AND RESULTS: Isg15-deficient mice were infected with control virus CVB3-39 or the cardiomyocyte-detargeted variant CVB3-1 containing miR-1 target sites. Cardiac detargeting profoundly reduced myocardial viral replication and prevented cardiomyocyte injury, inflammatory cell infiltration, and histological myocarditis. Selective suppression of myocardial viral replication did not substantially alter systemic viral dissemination or peripheral organ infection. Acute hepatitis and systemic cytokine responses developed similarly in CVB3-39- and CVB3-1-infected mice. Likewise, comparable reductions in cardiac output and ventricular filling parameters were observed in both infection groups during the acute phase of infection. Systemic metabolic alterations, including hypoglycemia, adipose tissue depletion, skeletal muscle wasting, and mortality, developed similarly with both viruses despite prevention of myocarditis with CVB3-1. DISCUSSION: During CVB3 infection in Isg15-deficient mice, myocardial viral replication is essential for local myocarditis but does not substantially influence systemic inflammatory and metabolic disease progression. Prevention of myocarditis failed to attenuate inflammatory activation, metabolic wasting, early cardiac dysfunction, or mortality. These findings suggest that systemic disease manifestations primarily reflect defective antiviral and immunometabolic adaptation rather than heart-driven amplification of disease.