Key result
Cardiomyocyte-detargeted Coxsackievirus B3 prevents myocarditis but fails to reduce systemic inflammation or mortality in mice.
Why the study?
To investigate whether selective prevention of myocardial viral replication attenuates systemic inflammatory and metabolic deterioration during CVB3 infection in Isg15-deficient mice.
Does selective prevention of myocardial viral replication attenuate systemic inflammatory and metabolic deterioration in Isg15-deficient mice infected with Coxsackievirus B3?
Does selective prevention of myocardial viral replication attenuate systemic inflammatory and metabolic deterioration in Isg15-deficient mice infected with Coxsackievirus B3?
In Isg15-deficient mice with Coxsackievirus B3 infection, systemic disease manifestations primarily reflect defective antiviral and immunometabolic adaptation rather than heart-driven amplification of disease.
Should not yet change practice; leaves open whether systemic wasting in viral myocarditis requires cardiac infection in humans.
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.
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Ochs et al. (2026) studied Coxsackievirus B3 infection (n=46). Cardiomyocyte-detargeted Coxsackievirus B3 (CVB3-1) vs. Replication-competent control virus (CVB3-39) was evaluated on Systemic inflammatory and metabolic disease progression. Cardiomyocyte-specific detargeting of Coxsackievirus B3 prevented myocarditis but failed to attenuate systemic inflammatory activation, metabolic wasting, early cardiac dysfunction, or mortality in Isg15-deficient mice.
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