NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis
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 sp…
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The TLR4, caspase-1, and NLRP3 pathways are upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3-only models and increase IL-1β and IL-18 levels in the heart.
“Another key pathway upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3only models is the TLR4, caspase-1, and NLRP3 pathways that increase IL-1 β and IL-18 levels in the heart. 124,146,152,156,161-164”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [163]
Cites
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Schultheiss, H.-P., Fairweather, D., Caforio, A. L. P., Escher, F., Hershberger, R. E., Lipshultz, S. E., Liu, P. P., Matsumori, A., Mazzanti, A., McMurray, J., et al. (2019) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0084-1 · Cited by 720 · see citing works
Self-citationMitochondria, Oxidative Stress and Innate Immunity
Chen, Y., Zhou, Z., & Min, W. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01487 · Cited by 315 · see citing works
“NLRs, including the NLRP1, NLRP3 and NLR family caspase recruitment domain (CARD) domain containing 4 (NLRC4) inflammasomes, are characterized by a central located NOD domain that is flanked at N-terminal CARD, pyrin domain (PYD), acidic transactivating domain, or baculovirus inhibitor repeat (BIR) (Franchi et al., 20…”
BackgroundCOVID-19, Myocarditis and Pericarditis
Fairweather, D., Beetler, D. J., Di Florio, D. N., Musigk, N., Heidecker, B., & Cooper, L. T. (2023) · Circulation Research · doi:10.1161/circresaha.123.321878 · Cited by 181 · see citing works
Jain, A., Bruno, K. A., Matsumori, A., Cooper, L. T., Yamani, M., & Fairweather, D. (2022) · Comprehensive Pharmacology · doi:10.1016/b978-0-12-820472-6.00091-8 · Cited by 1 · see citing works
- Authors
- Tschöpe, C., Müller, I., Xia, Y., Savvatis, K., Pappritz, K., Pinkert, S., Lassner, D., Heimesaat, M. M., Spillmann, F., Miteva, K., Bereswill, S., Schultheiss, H.-P., Fechner, H., Pieske, B., Kühl, U., & Van Linthout, S.
- Affiliations
- Deutsches Herzzentrum der Charité (DE)
- 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...
- ORCID
- Venue
- Circulation: Heart Failure
- Published
- 2017-09
- Volume
- 10
- Issue
- 9
- ISSN
- 1941-3289 (ISSN-L)
- 1941-3297
- OpenAlex
- W2753983277
- Cited by
- 88
- References
- 2
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 4 · 2021: 10 · 2020: 15 · 2019: 13 · 2018: 6 · 2017: 2
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- NOD2, coxsackievirus B3, viral myocarditis, NLRP3 inflammasome, innate immunity, cardiac inflammation, myocardial fibrosis, apoptosis, CAR receptor, caspase-1, IL-1β, left ventricular function
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cell Line, Coxsackievirus Infections, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Myocarditis, Myocardium, Phenotype, Transfection, Signal Transduction, Up-Regulation, Case-Control Studies, Apoptosis, Mice, Knockout, Genetic Predisposition to Disease, Caspase 1, Enterovirus B, Human, RNA Interference, Apoptosis Regulatory Proteins, CARD Signaling Adaptor Proteins, Nod2 Signaling Adaptor Protein, Interleukin-1beta, Host-Pathogen Interactions
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