Major 5′terminally deleted enterovirus populations modulate type I IFN response in acute myocarditis patients and in human cultured cardiomyocytes
M. Glenet, Yohan N’Guyen, A. Mirand, C. Henquell, Anne-Laure Lebreil, Fatma Berri, Firouzé Bani‐Sadr, Bruno Lina, I. Schuffenecker, Laurent Andréoletti, The French Enterovirus Myocarditis Study Group (FEMSG), A. Mirand, C. Henquell, Marie‐Laure Mathieu, Ellia Mezgueldi, Matthieu Verdan, Pascal Motreff, Bruno Lina, I. Schuffenecker, Samira Fafi‐Kremer, Quentin Lepiller, P Bruneval
Abstract
Major 5'terminally deleted (5'TD) group-B enterovirus (EV-B) populations were identified in heart biopsies of patients with fulminant myocarditis or dilated cardiomyopathy suggesting that these 5'TD forms are key drivers of host-cell interaction in EV cardiac infections. To date, early emergence of EV-B 5'TD forms and its impact on type 1 IFN response during acute myocarditis remains unknown. Using quantitative RACE-PCR assay, we identified major EV-B 5'TD RNA populations in plasma or heart samples of acute myocarditis cases. Deletions identified within the 5' non-coding region of EV-B populations only affected secondary-structural elements of genomic RNA domain I and were distinguished in two major groups based on the extent of RNA structural deletions. Proportions of these two respective EV-B 5'TD population groups were positively or negatively correlated with IFN-β levels in plasma samples of myocarditis patients. Transfection of synthetic CVB3/28 RNAs harboring various 5'terminal full-length or deleted sequences into human cultured cardiomyocytes demonstrated that viral genomic RNA domain I possessed essential immunomodulatory secondary-structural elements responsible for IFN-β pathway induction. Overall, our results highlight the early emergence of major EVB-TD populations which deletions affecting secondary-structures of RNA domain I can modulate innate immune sensing mechanisms in cardiomyocytes of patients with acute myocarditis.