Molecular mechanisms and cellular consequences of .. (CARDIOVIR)
Molecular mechanisms and cellular consequences of enterovirus persistence in cardiomyocytes
Start date: Mar 1, 2014,
End date: Jun 1, 2017
Enteroviruses (EV) are small naked single-stranded positive RNA viruses of approximately 7,400 nucleotides. Their genome is flanked on the 5' end by a non-coding region (NCR), which is crucial for the initiation of the replication and translation of the viral genome. Enteroviruses are common human pathogens, transmitted through fecal-oral and respiratory routes. Although the majority of EV infections remain asymptomatic, these viruses, especially group B coxsackieviruses (CVB), are considered to be a common cause of acute myocarditis in children and young adults, a disease which is a precursor to 10-20% of chronic myocarditis cases as well as dilated cardiomyopathy (DCM, prevalence = 7 cases / 100,000, second leading cause of heart transplantation worldwide after ischemic heart disease). However, the viral molecular mechanisms involved in the progression of acute myocarditis to chronic myocarditis and subsequently to DCM are currently poorly understood, thereby limiting the development of new specific therapeutic strategies. In 2011, our research team (EA-4684 CardioVir/FRS CAP-santé, University of Reims Champagne-Ardenne) reported CVB strains presenting with genomic 5’ terminal deletions ranging in size from 15 to 35 nucleotides in explanted heart tissue collected from patients suffering from idiopathic DCM. These deletions could explain how the virus can persist in the heart long after the acute infection leading to the development of chronic cardiomyopathies. The objectives of this proposal are to determine the mechanisms by which deleted EV ensure the translation and replication of their genomes and to assess the effects of persistent infection on the structures and functions of infected cardiac myocytes. A better understanding of the molecular mechanisms implicated in viral persistence will stimulate the research into new therapeutic strategies to prevent and treat chronic infections caused by EV.
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