Key result
CV-B3 infection causes 100% mortality in neonatal mice, driven by higher CAR splice variant expression.
Why the study?
Children are more likely to experience severe manifestations of Coxsackievirus B3 infection, but the molecular basis of this age-dependent susceptibility is poorly understood.
Absolute Event Rate: 0% vs 100%
Heightened susceptibility to CV-B3-induced myocarditis and encephalitis in neonatal mice is driven by age-dependent high expression of specific CAR splice variants, which facilitates rapid viral replication and fatal NLRP3 inflammasome-mediated inflammation.
Hypothesis-generating for CAR splice variants in neonatal CV-B3 myocarditis; leaves open translation to human disease and therapies.
Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates.
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Zhang et al. (2025) studied CV-B3-induced encephalitis and myocarditis. Coxsackievirus B3 (CV-B3) infection vs. PBS control was evaluated on Survival rate following CV-B3 infection. CV-B3 infection caused 100% mortality in 7-day-old mice compared to 100% survival in 30-day-old mice, driven by an age-dependent progressive decline in CV-B3-binding CAR1 and CAR2 splice variants.
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