Carsten Tschöpe1, Irene Müller2, Yu Xia2, Konstantinos Savvatis2, Kathleen Pappritz2, Sandra Pinkert2, Dirk Lassner2, Markus M Heimesaat2, Frank Spillmann2, Kapka Miteva2, Stefan Bereswill2, Heinz-Peter Schultheiss2, Henry Fechner2, Burkert Pieske2, Uwe Kühl2, Sophie Van Linthout2. 1. From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.). carsten.tschoepe@charite.de. 2. From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.).
Abstract
BACKGROUND: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1β (interleukin-1β) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.
BACKGROUND: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3mice compared with wild-type CVB3mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1β (interleukin-1β) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS:NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3myocarditis.
Authors: Daniel Limonta; Lovely Dyna-Dagman; William Branton; Valeria Mancinelli; Tadashi Makio; Richard W Wozniak; Christopher Power; Tom C Hobman Journal: Antimicrob Agents Chemother Date: 2021-07-16 Impact factor: 5.191