Zika virus infection in neonatal mice disrupts connexin 43 and induces cardiac inflammation, implicating viral myocarditis in neonatal pathogenesis.

Zika virus (ZIKV) is primarily transmitted through mosquito bites and, occasionally, via breast milk, making postnatal ZIKV infections common among newborns and infants, particularly in tropical regions. Previous studies, including ours, have demonstrated that neonatal ZIKV infection can be fatal, highlighting a severe health issue of ZIKV in newborns. However, the pathogenesis and functional outcomes of postnatal ZIKV infection remain largely unexplored. The mechanisms underlying organ failure in infected neonates are still unknown. Here, we investigated postnatal ZIKV (PRVABC59) infection in neonatal mice and found significant cardiac abnormalities. Electrocardiogram (EKG) analysis revealed extended P-R intervals (indicative of the atrioventricular block), widened QRS complexes (suggesting intraventricular block), and elevated ST wave (a biomarker of myocardium impairment), implying defects in myocardial conduction. In addition, ZIKV infection caused increased levels of cTnT, cTnI, CK, CK-MB, CCL2, CXCL9, and CXCL10-biomarkers associated with cardiovascular diseases and infarction-like myocardial pathology. To further elucidate the underlying mechanisms, we analyzed cytokine and chemokine responses and observed a significant increase in multiple inflammatory mediators, including M-CSF, LIF, IL-6, IL-15, CCL2, CCL4, CCL5, CCL11, CXCL1, CXCL9, CXCL10, TNF-α, and VEGF. Notably, ZIKV infection also led to the degradation of connexin 43 (Cx43), a critical protein involved in heart development and intercellular communication among myocardial cells. In summary, our neonatal mouse model of ZIKV infection suggests that ZIKV-induced myocarditis and cardiac dysfunction may contribute to fatal outcomes in newborns. These findings provide new insights into ZIKV pathogenesis and underscore the need for further research into its impact on the cardiovascular system in early life.IMPORTANCEZika virus (ZIKV) is a known teratogen responsible for microcephaly in neonates born to mothers infected during pregnancy. Mouse models have been instrumental in elucidating ZIKV pathogenesis; however, most published studies utilize interferon (IFN)-compromised animals, either genetically modified or antibody-treated. In this study, we employed immunocompetent neonatal mice to investigate postnatal ZIKV infection and uncovered its impact on heart function. We detected high viral loads in heart tissue at early, middle, and late stages of infection using RT-qPCR. Electrocardiogram (EKG) analysis demonstrated cardiac dysfunction, including conduction abnormalities. At the same time, elevated levels of cTnT, cTnI, CK, CK-MB, LDH, α-HBDH, CCL2, and CXCL10-hallmarks of cardiovascular pathology-suggested inflammatory responses associated with heart failure. These findings indicate that neonatal mortality following postnatal ZIKV infection may be driven by virus-induced cardiac dysfunction. Our results provide new insights into ZIKV pathogenesis, suggesting that postnatal ZIKV infection poses a significant risk for severe cardiac disease in neonates.