Unveiling Mechanisms of ZIKV-Induced Cardiac Dysfunction in a mouse model - Viral-induced heart disease in pediatric patients presents substantial challenges, given the limited treatment options available. Recent studies have highlighted cases of flavivirus-induced myocarditis in clinical settings supported by relevant animal models. Neonatal mice infected with the Zika virus (ZIKV), a flavivirus, exhibit severe heart dysfunction, organ impairment, and mortality, revealing previously underestimated clinical risks associated with neonatal ZIKV infection. Animals and humans with microcephaly can survive despite neuronal damage, suggesting that neuronal injury alone is not fatal. This implies that damage to other organs may contribute to ZIKV-associated mortality. Therefore, this R16 grant proposal aims to unravel the intricate mechanisms behind ZIKV-induced cardiac dysfunction through comprehensive in vitro and in vivo investigations. The overarching objective is to deepen our understanding of viral heart disease pathogenesis and identify novel therapeutic targets for effective interventions. Recent groundbreaking research has shed light on the lethal effects of ZIKV infection in neonatal mice. These findings underscore the complex interplay between ZIKV infection and cardiomyocyte dysfunction, highlighting potential links between viral replication, inflammation, and cardiac abnormalities. Our central hypothesis posits that ZIKV replication within the heart triggers the degradation of crucial cardiac proteins and provokes inflammation, ultimately leading to neonatal heart dysfunction. To test this hypothesis, we have designed two specific aims that explore distinct facets of heart damage caused by ZIKV infection: 1) Unraveling the mechanisms underlying ZIKV-induced heart injury. We will investigate the impact of ZIKV on gap junction conductance in neonatal mouse cardiomyocytes, conduct in vivo studies to elucidate the inflammatory damage caused by ZIKV on cardiomyocytes, and examine potential ischemic effects of ZIKV on heart tissue. 2) Investigating ZIKV-induced degradation of crucial cardiomyocyte proteins. We will explore interactions between ZIKV and cellular proteins associated with cardiomyocyte functions (in vitro) and assess the impact of postnatal ZIKV infection on neonatal mice's centrosomes and Cx43 proteins (in vivo). This multifaceted research will be spearheaded by Dr. Qiyi Tang, a virologist with extensive experience in ZIKV research, supported by a team of experts, including Dr. Daniela Cihakova (cardiac immunology) and Dr. Pal Pacher (cardiovascular inflammation). This project represents a critical step toward addressing the urgent need for effective treatments for viral heart diseases in pediatric patients. The innovative proof of concept and experimental approaches, combining the complementary expertise of this strong collaborative team, hold great promise for success. We will actively recruit and mentor graduate and undergraduate students, offering them immersive experiences and exposure to the forefront of research in virology and cardiac pathology.
