NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis

Tschöpe, Carsten; Müller, Irene; Xia, Yu; Savvatis, Konstantinos; Pappritz, Kathleen; Pinkert, Sandra; Laßner, Dirk; Heimesaat, Markus M.; Spillmann, Frank; Miteva, Kapka; Bereswill, Stefan; Schultheiss, Heinz‐Peter; Fechner, Henry; Pieske, Burkert; Kühl, Uwe; Linthout, Sophie Van

doi:10.1161/circheartfailure.117.003870

Cited by 71 publications

(61 citation statements)

References 32 publications

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“…Immune cells that contribute to remodelling include mast cells, macrophages (M2 macrophages, also known as alternatively activated macrophages, and myeloidderived suppressor cells), T helper 2 (T H 2) and T H 17 cells and, in the case of autoimmune aetiologies, B cells that produce autoantibodies that form immune complexes with self-antigens and complement components 64,65 . Immune cells release cytokines, such as transforming growth factor-β1 (TGFβ1), IL-4, IL-1β, IL-17A, IL-33 and tumour necrosis factor (TNF), among other mediators, that promote remodelling, collagen deposition and fibrosis [66][67][68][69][70][71] . Fibrosis is a consequence of inflammation at the site of tissue damage and is the characteristic pathological feature of DCM aside from dilatation 8,62 .…”

Section: Inflammationmentioning

confidence: 99%

Dilated cardiomyopathy

Schultheiss

Fairweather

Caforio

et al. 2019

Nat Rev Dis Primers

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Section: Inflammationmentioning

confidence: 99%

Dilated cardiomyopathy

Schultheiss

Fairweather

Caforio

et al. 2019

Nat Rev Dis Primers

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479

381

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“…adaptive immune system, which is associated with diffuse inflammation of the myocardium (3)(4)(5). Activated monocytes, macrophages, and T-and B-lymphocytes derived from secondary lymphoid organs, like the spleen, are thereby recruited into the heart-cardiosplenic axis-to initiate an orchestra of antiviral and inflammatory defense responses (6); however, this immune response can induce cardiac-damaging mechanisms when uncontrolled and hyperactive-for example, cardiac fibrosis-and may progress to dilated cardiomyopathy (7).…”

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confidence: 99%

Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

et al. 2018

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Regulatory T (T) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic T administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic T cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + T mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6CCCR2Cx3Cr1 monocytes and higher retention of proinflammatory Ly6CCCR2Cx3Cr1 monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + T compared with CVB3 + PBS mice. Coculture of T cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of T cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6CCCR2Cx3Cr1 subset. T-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + T compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + T mice compared with CVB3 + PBS mice. In summary, adoptive T transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

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“…CVB3 infection also activates the NLRP3 inflammasome (27). However, unlike the closely related enterovirus, EV-A71 (HEV-A genus), for which the NLRP3 inflammasome plays a defensive role against virus infection (18)(19)(20), it was reported that inhibition of caspase-1 activity or knockdown of NOD2 in mice alleviates CVB3-induced myocardial damage (27,28). These observations suggest a possible pathogenic role for NLRP3 inflammasome in CVB3 infection; however, direct evidence is lacking.…”

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confidence: 99%

NLRP3 deficiency exacerbates enterovirus infection in mice

et al. 2018

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The role for the NOD-like receptor (NLR) P3 inflammasome in enterovirus infection remains controversial. Available data suggest that the NLRP3 inflammasome is protective against enterovirus A71 but detrimental to the host during coxsackievirus B3 (CVB3) infection. CVB3 is a common etiologic agent associated with myocarditis and pancreatitis. Previous findings on the role of NLRP3 in CVB3 were based primarily on indirect evidence. Here, we utilized NLRP3 knockout mice as well as immune and cardiac cells to investigate the direct interplay between CVB3 infection and NLRP3 activation. We demonstrated that NLRP3 knockout mice exhibited more severe disease phenotype after CVB3 infection (significantly higher virus titers), increased myocardial, and pancreatic damage, as well as markedly impaired cardiac function compared to nontransgenic control mice. We further showed that NLRP3 activity was enhanced during early stage of CVB3 infection, as evidenced by increased gene expression and/or secretion of IL-1β and caspase-1. Finally, we demonstrated that CVB3 inactivates the NLRP3 inflammasome by degrading NLRP3 and its upstream serine/threonine-protein kinase receptor-interacting protein 1/3 via the proteolytic activity of virus-encoded proteinases. Taken together, our results reveal the functional significance of NLRP3 in host antiviral immunity against CVB3 infection and the mechanisms by which CVB3 has evolved to counteract the host defense response.-Wang, C., Fung, G., Deng, H., Jagdeo, J., Mohamud, Y., Xue, Y. C., Jan, E., Hirota, J. A., Luo, H. NLRP3 deficiency exacerbates enterovirus infection in mice.

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NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis

Abstract: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.

Cited by 71 publications

References 32 publications

Dilated cardiomyopathy

Dilated cardiomyopathy

Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

NLRP3 deficiency exacerbates enterovirus infection in mice

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