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- Title
Major Group-B Enterovirus populations deleted in the noncoding 5' region of genomic RNA modulate activation of the type I interferon pathway in cardiomyocytes and induce myocarditis.
- Authors
Callon, Domitille; Glenet, Marie; Lebreil, Anne-Laure; Heng, Laetitia; Bouland, Nicole; Fichel, Caroline; Fornes, Paul; Andreoletti, Laurent; Berri, Fatma
- Abstract
Major 5'-terminally deleted (5'TD) RNA forms of group-B coxsackievirus (CVB-5'TD) has been associated with myocarditis in both mice and humans. Although it is known that interferon-β (IFN-β) signaling is critical for an efficient innate immune response against CVB-induced myocarditis, the link between CVB-5'TD RNA forms and type I IFN signaling in cardiomyocytes remains to be explored. In a mouse model of CVB3/28-induced myocarditis, major early-emerging forms of CVB-5'TD RNA have been characterized as replicative viral populations that impair IFN-β production in the heart. Synthetic CVB3/28 RNA forms mimicking each of these major 5'TD virus populations were transfected in mice and have been shown to modulate innate immune responses in the heart and to induce myocarditis in mice. Remarkably, transfection of synthetic viral RNA with deletions in the secondary structures of the 5'-terminal CVB3 RNA domain I, modifying stem-loops "b", "c" or "d", were found to impair IFN-β production in human cardiomyocytes. In addition, the activation of innate immune response by Poly(I:C), was found to restore IFN-β production and to reduce the burden of CVB-5'TD RNA-forms in cardiac tissues, thereby reducing the mortality rate of infected mice. Overall, our results indicate that major early-emerging CVB3 populations deleted in the domain I of genomic RNA, in the 5' noncoding region, modulate the activation of the type I IFN pathway in cardiomyocytes and induce myocarditis in mice. These findings shed new light on the role of replicative CVB-5'TD RNA forms as key pathophysiological factors in CVB-induced human myocarditis. Author summary: Myocarditis is an inflammatory disease of the heart. Viruses or post-viral immune mediated response are the main causes of myocarditis. Human group B enteroviruses, specifically Coxsackievirus B3 (CVB3), are common infectious causes of acute myocarditis in the young. Early emergence and maintenance of major 5'terminally deleted RNA forms of CVB have been associated with acute and chronic myocarditis in both mice and humans. To achieve viral genome maintenance in the cardiac cells, viruses could modulate innate immunity activation. Here, we report on major early-emerging CVB3 populations deleted in the 5'non-coding region of viral genomic RNA that modulate the activation of the type I interferon pathway in cardiomyocytes and cause myocarditis in mice. Activating the innate immune sensors after CVB3 infection protects mice from CVB3-induced myocarditis and shall promote further studies in immunotherapies in viral acute and chronic myocarditis.
- Subjects
TYPE I interferons; INTERFERONS; MYOCARDITIS; RNA; VIRAL genomes; HEART cells; HAIRPIN (Genetics)
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 5, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1012125