Group B Enteroviruses (Picornaviridae) are non-enveloped, single-stranded RNA viruses of positive polarity. These common and ubiquitous pathogens are responsible for common acute or persistent infections in various human target tissues including the cardiovascular system. Their (+) RNA genome of 7.5 kpb is composed of a non-coding region at the 5' end that is crucial for the initiation of viral replication and translation mechanisms.
Natural viral forms with terminal deletions of variable length in the 5' non-coding region (5'NC) have been characterized using molecular approaches (NGS) in murine or human EV-B induced infections by our team.
The CardioVir team studies the viral and immunological mechanisms involved in acute and persistent EV-B viral infections and their role in the development of unexplained cardiac pathologies.
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1/ Viruses and sudden cardiac death (SCD).
2/ Impact of viral infections in the development of cardiomyopathies (Myocarditis, CMD).
3/ Study of the inflammatory response and modulation of the type I interferon response by viruses with cardiovascular tropism (EV-B).
4/ Impact of the Epitranscriptome of the genome of RNA+ viruses (EV-B) on the infection of cardiovascular target cells.
Funding: French Federation of Cardiology (FFC)
The incidence of myocarditis is approximately 1.5 million cases per year worldwide. In the United States and Europe, this cardiomyopathy results mainly from infection of cardiac tissue by human group B enteroviruses, and is considered one of the major causes of sudden cardiac death or dilated cardiomyopathy (DCM) in children and young adults. Currently, the virological and immunological mechanisms that regulate the progression of acute viral myocarditis to the severe or fulminant form or to the chronic phase that leads to DCM remain unknown and limit the development of new targeted therapeutic strategies.
Our viro-clinical investigations (human sample banks already constituted) and experimental investigations (in vitro in cultured human heart cells and in vivo in DBA2/J mice) will allow us to (I) to identify in group B Enteroviruses (CVB3) the immunogenic sequences and RNA structures of the 5'NC region capable of activating the type I interferon pathway in humans; (II) to determine the main RLR-type receptors (RIG-1, MDA5, LGP2) in human cardiac cells capable of binding the viral RNA structures identified previously (objective I); (III) to study the modulation of type 1 IFN pathways by specific agonists of innate immunity receptors (identified in objective II) and the impact of this activation on cardiac injury scores and mortality of DBA2/J mice with acute or chronic CVB3/28 myocarditis.
The immunovirological results obtained during the study of the acute phase of enterovirus myocarditis will allow the identification of new virological or immunological biomarkers that will allow the detection of patients at risk of severe or chronic clinical forms in clinical practice. Moreover, our experimental data obtained in the mouse model of CVB3 myocarditis could eventually allow to propose new immunomodulatory treatments (immunotherapies) adapted to the stage of evolution and the clinical severity of viral myocarditis.
Key words: myocarditis, innate immune response, Enterovirus, type 1 interferon, 5'NC.
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To infect cardiomyocytes, the cardiotropic virus must cross the vascular endothelium, which thus represents a first line of antiviral defense. Endothelial cells have been identified as the conductor of the inflammatory response during viral infection. Thus, modulation of the excessive inflammatory response at the vascular endothelium induced by CVB3 during acute myocarditis could help prevent the development of fulminant forms, as well as progression to DCM.
Chemical modulators of cellular receptors in the Sphingosine-1 Phosphate family, S1PR1-S1PR5, play key roles in the immune response to diseases such as multiple sclerosis and influenza. Activation of signaling pathways by S1P exerts powerful cardioprotective and immunomodulatory actions, regulating vascular tone and the endothelial barrier10. At low concentrations, S1P is known to enhance endothelial barrier integrity via S1P1R, and at high levels to disrupt the endothelial barrier via S1P3R. Experimental studies have shown that the concentration of S1P in blood regulates inflammation. This concept is well documented in several pathologies. Experimental studies have shown that pharmacological activation of S1P receptors (S1PR) by an agonist was associated with a protective effect in a mouse model of myocarditis induced by the murine virus ECMV.
However, the consequences of CVB3 infection on S1P secretion and S1P receptor activation remain unknown in humans, and therefore remain to be explored.
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Funding: Fonds régional de coopération pour la recherche-APP 2021-2023, PI: Yuri Motorin (Université de Lorraine) ; Co-PI: Carine Meignin (Université de Strasbourg) and Laurent Andreoletti (66,6K euros from Feder funds).
Collaborations:
RNA modifications, commonly referred to as epitranscriptome, are observed on specific residues of cellular RNAs and play a key role for their maturation and functionality. Among more than one hundred and fifty described chemical modifications, methylation of nucleotides at different positions is the most abundant. In the last decade, the development of new detection approaches by high-throughput genome-wide sequencing has led to the identification of mRNA methylation providing a new level of regulation of gene expression.
However, very few studies have been devoted so far to viral RNA modifications and, despite the identification of some RNA modifications present in viruses, little is known about their roles in virus infection and propagation. Some modifications of viral RNAs appear today fundamental for the regulation of arboviruses (ZIKA and Dengue) and other viruses. This ambitious project has an integrative dimension, since it combines the mapping of the epitranscriptome of viral RNAs with genetic and molecular virology approaches.
The ViroMOD project brings together partners in Lorraine, Alsace and Champagne-Ardenne who are scientists with international visibility and diverse backgrounds including RNA biologists (IMoPA, Nancy), experts in molecular virology and insect genetics (UPR9022, Strasbourg) and in medical virology (UMR-S 1320, ex-EA-4684, Reims). The ViroMOD project will generate complementary expertises by integrating different technological approaches and biological models.
The project has three scientific objectives: to map post-transcriptional modifications of genomic RNAs (gRNAs) of positive polarity for CVB3 and SARS-Cov-2 viruses; to study the impact of gRNA modifications on viral genome replication and maturation; and to study the detection of modified viral RNAs by the host innate immune system
In the field of molecular virology, the comprehensive characterization of the epitranscriptome of viral RNAs will be crucial for a better understanding of the defense mechanisms against these infections. Modulation of viral RNA modifications may help to restore the efficiency of recognition mechanisms as well as the elimination of the virus, or, at least, limit its spread to a very large extent.
Key words: Infection, molecular virology, epitranscriptomics, RNA modification
