Acute viral myocarditis (WP4298)

Homo sapiens

Viral myocarditis is a rare cardiac disease associated with the inflammation and injury of the myocardium. The downstream effects are a product of cooperation between viral processes and both the adaptive as innate host's immune response. Acute appearance of myocarditis is mostly idiopathic, i.e. of unknown origin. Primarily established on clinical observation and limited epidemiologic studies. Most studied cases are coxsackie, adeno and human immunodeficiency virus. Grey compartments describe extracellular matrix. Direct lines indicate downstream effects and dashed lines indicate speculative research.
last edited


Olivier Traets , Friederike Ehrhart , Egon Willighagen , Kristina Hanspers , Marvin Martens , Eric Weitz , and Finterly Hu

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens


Diseases Rare Diseases


Pathway Ontology: myocarditis pathway disease pathway cardiomyopathy pathway

Disease Ontology: viral infectious disease myocarditis

Cell Type Ontology: cardiac muscle cell


Label Type Compact Identifier Comment
ganglioside GM1 Metabolite chebi:18216
prostaglandin E2 Metabolite chebi:606564
RAF-1 Metabolite hmdb:HMDB0003213
Herbimycin A Metabolite chebi:5674
glycophosphatidylinositol Metabolite chebi:63419
Ca2+ Metabolite hmdb:HMDB0000464
reactive oxygen species generators Metabolite chebi:70982
glycophosphatidylinositol Metabolite chebi:63419
Ca2+ Metabolite hmdb:HMDB0000464
SOCS1 GeneProduct ensembl:ENSG00000185338
IFNG GeneProduct ensembl:ENSG00000111537
TGFB1 GeneProduct ensembl:ENSG00000105329
JAK1 GeneProduct ensembl:ENSG00000162434
STAT1 GeneProduct ensembl:ENSG00000115415
IL10 GeneProduct ensembl:ENSG00000136634
IL6 GeneProduct ensembl:ENSG00000136244
STAT3 GeneProduct ensembl:ENSG00000168610
EIF4G2 GeneProduct ensembl:ENSG00000110321
ACTB GeneProduct ensembl:ENSG00000075624
BAX GeneProduct ensembl:ENSG00000087088
SGCB GeneProduct ensembl:ENSG00000163069
ILK GeneProduct ensembl:ENSG00000166333
CD4 GeneProduct ensembl:ENSG00000010610
FYN GeneProduct ensembl:ENSG00000010810
MMP9 GeneProduct ensembl:ENSG00000100985
RAC2 GeneProduct ensembl:ENSG00000128340
ABL1 GeneProduct ensembl:ENSG00000097007
BCL2L1 GeneProduct ensembl:ENSG00000171552 BCL-XL
CASP2 GeneProduct ensembl:ENSG00000106144
CASP6 GeneProduct ensembl:ENSG00000138794
CASP7 GeneProduct ensembl:ENSG00000165806
CCR5 GeneProduct ensembl:ENSG00000160791
TLR3 GeneProduct ensembl:ENSG00000164342 low expression
Type your comment here
CYCS GeneProduct ensembl:ENSG00000172115
PTCRA GeneProduct ensembl:ENSG00000171611
IL1 GeneProduct pfam:PF00340 IL1 protein family
CHRAC1 GeneProduct ensembl:ENSG00000104472
AIF1 GeneProduct ensembl:ENSG00000204472
CCND1 GeneProduct ensembl:ENSG00000110092
TICAM1 GeneProduct hgnc.symbol:TICAM1
SOS1 GeneProduct ensembl:ENSG00000115904
MAPK1 GeneProduct ensembl:ENSG00000100030
RASA1 GeneProduct ensembl:ENSG00000145715
SGCA GeneProduct ensembl:ENSG00000108823
DFFB-45 GeneProduct ensembl:ENSG00000169598
GSK3B GeneProduct ensembl:ENSG00000082701
AKT1 GeneProduct ensembl:ENSG00000142208
CD55 GeneProduct ensembl:ENSG00000196352
SGCD GeneProduct ensembl:ENSG00000170624
HLA-DMA GeneProduct ensembl:ENSG00000204257
ENDOG GeneProduct ensembl:ENSG00000167136
TLR4 GeneProduct ensembl:ENSG00000136869 low expression
Type your comment here
PYCARD GeneProduct ensembl:ENSG00000103490 Adaptor protein ASC
DFFA/ICAD GeneProduct ensembl:ENSG00000160049
PIK3 GeneProduct ensembl:ENSG00000145675
Cd28 GeneProduct ncbigene:12487
ITGAL GeneProduct ensembl:ENSG00000005844
LAMA2 GeneProduct ensembl:ENSG00000196569
CREB1 GeneProduct ensembl:ENSG00000118260
CXCR4 GeneProduct ensembl:ENSG00000121966
ITGB2 GeneProduct ensembl:ENSG00000160255
NFKB2 GeneProduct ensembl:ENSG00000077150
CASP3 GeneProduct ensembl:ENSG00000164305
IL12A GeneProduct ensembl:ENSG00000168811
KRT8 GeneProduct ensembl:ENSG00000170421
MYH6 GeneProduct ensembl:ENSG00000197616
RAC3 GeneProduct ensembl:ENSG00000169750
DMD GeneProduct ensembl:ENSG00000198947
BCL2 GeneProduct ensembl:ENSG00000171791
DAP5 GeneProduct ensembl:ENSG00000110321
DAG1-B GeneProduct ncbigene:1605
TLR5 GeneProduct ensembl:ENSG00000187554 high expression
Type your comment here
CASP9 GeneProduct ensembl:ENSG00000132906
CCR3 GeneProduct ensembl:ENSG00000183625
DAG1-a GeneProduct ensembl:ENSG00000173402
EIF4G1 GeneProduct ensembl:ENSG00000114867
SGCG GeneProduct ensembl:ENSG00000102683
CD40LG GeneProduct ensembl:ENSG00000102245
BNIP2 GeneProduct ensembl:ENSG00000140299
ABL2 GeneProduct ensembl:ENSG00000143322
MAPK3 GeneProduct ensembl:ENSG00000102882 alternative name ERK1
CD80 GeneProduct ensembl:ENSG00000121594
CAV1 GeneProduct ensembl:ENSG00000105974
PTCRA GeneProduct ensembl:ENSG00000171611
CAAP1 GeneProduct ensembl:ENSG00000120159
PARP1 GeneProduct ensembl:ENSG00000143799
PABPC1 GeneProduct ensembl:ENSG00000070756
MAPK1 GeneProduct ensembl:ENSG00000100030 alternative name ERK2
IL12B GeneProduct ensembl:ENSG00000113302
Nitric oxide synthase Protein uniprot:B3VK56
Endothelin-1 Protein uniprot:P05305
CASP8 Protein ensembl:ENSG00000064012
ATF-2 Protein uniprot:P16951
DAF Protein uniprot:A0A1U8D6D6 Dispensible for productive replication
NOD2 Protein uniprot:E9PLF7
p53 Protein uniprot:A0A0R4J1K8
TNF-a Protein ensembl:ENSG00000232810
BH3 Bid Protein uniprot:A8ASI8
Catenin beta-1 Protein uniprot:E9PW26
JNK1 Protein uniprot:A0A087WVY6
SRC Protein ensembl:ENSG00000197122
TNFRSM5 Protein uniprot:P27512
MHC-1 Protein uniprot:A0A024RCL3
CARCXADR Protein ensembl:ENSG00000154639
IL1 Protein uniprot:G3V169
c-Jun Protein uniprot:Q9WVI9
Perforin-1 Protein uniprot:P10820
IL2 Protein uniprot:P60568
Dystrophin Protein uniprot:A2A9Z1
cd86 Protein uniprot:D3Z363
BH3 Bid Protein uniprot:A8ASI8


  1. Bowles NE, Richardson PJ, Olsen EG, Archard LC. Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet. 1986 May 17;1(8490):1120–3. PubMed Europe PMC Scholia
  2. Iizuka N, Kuge S, Nomoto A. Complete nucleotide sequence of the genome of coxsackievirus B1. Virology. 1987 Jan;156(1):64–73. PubMed Europe PMC Scholia
  3. Zhang Y, Schneider RJ. Adenovirus inhibition of cell translation facilitates release of virus particles and enhances degradation of the cytokeratin network. J Virol. 1994 Apr;68(4):2544–55. PubMed Europe PMC Scholia
  4. Barry WH. Mechanisms of immune-mediated myocyte injury. Circulation. 1994 May;89(5):2421–32. PubMed Europe PMC Scholia
  5. Muckelbauer JK, Kremer M, Minor I, Diana G, Dutko FJ, Groarke J, et al. The structure of coxsackievirus B3 at 3.5 A resolution. Structure. 1995 Jul 15;3(7):653–67. PubMed Europe PMC Scholia
  6. Huber M, Selinka HC, Kandolf R. Tyrosine phosphorylation events during coxsackievirus B3 replication. J Virol. 1997 Jan;71(1):595–600. PubMed Europe PMC Scholia
  7. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997 Feb 28;275(5304):1320–3. PubMed Europe PMC Scholia
  8. Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997 Apr 18;89(2):175–84. PubMed Europe PMC Scholia
  9. Leiden JM. The genetics of dilated cardiomyopathy--emerging clues to the puzzle. N Engl J Med. 1997 Oct 9;337(15):1080–1. PubMed Europe PMC Scholia
  10. Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest. 1998 Jun 1;101(11):2415–26. PubMed Europe PMC Scholia
  11. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998 Aug 21;94(4):491–501. PubMed Europe PMC Scholia
  12. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med. 1998 Oct 15;339(16):1093–9. PubMed Europe PMC Scholia
  13. Wang X, Bergelson JM. Coxsackievirus and adenovirus receptor cytoplasmic and transmembrane domains are not essential for coxsackievirus and adenovirus infection. J Virol. 1999 Mar;73(3):2559–62. PubMed Europe PMC Scholia
  14. Huber M, Watson KA, Selinka HC, Carthy CM, Klingel K, McManus BM, et al. Cleavage of RasGAP and phosphorylation of mitogen-activated protein kinase in the course of coxsackievirus B3 replication. J Virol. 1999 May;73(5):3587–94. PubMed Europe PMC Scholia
  15. Bewley MC, Springer K, Zhang YB, Freimuth P, Flanagan JM. Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR. Science. 1999 Nov 19;286(5444):1579–83. PubMed Europe PMC Scholia
  16. Henke A, Launhardt H, Klement K, Stelzner A, Zell R, Munder T. Apoptosis in coxsackievirus B3-caused diseases: interaction between the capsid protein VP2 and the proapoptotic protein siva. J Virol. 2000 May;74(9):4284–90. PubMed Europe PMC Scholia
  17. Seipelt J, Liebig HD, Sommergruber W, Gerner C, Kuechler E. 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells. J Biol Chem. 2000 Jun 30;275(26):20084–9. PubMed Europe PMC Scholia
  18. Badorff C, Lee GH, Knowlton KU. Enteroviral cardiomyopathy: bad news for the dystrophin-glycoprotein complex. Herz. 2000 May;25(3):227–32. PubMed Europe PMC Scholia
  19. He Y, Chipman PR, Howitt J, Bator CM, Whitt MA, Baker TS, et al. Interaction of coxsackievirus B3 with the full length coxsackievirus-adenovirus receptor. Nat Struct Biol. 2001 Oct;8(10):874–8. PubMed Europe PMC Scholia
  20. Liu QN, Reddy S, Sayre JW, Pop V, Graves MC, Fiala M. Essential role of HIV type 1-infected and cyclooxygenase 2-activated macrophages and T cells in HIV type 1 myocarditis. AIDS Res Hum Retroviruses. 2001 Oct 10;17(15):1423–33. PubMed Europe PMC Scholia
  21. Barbaro G, Lipshultz SE. Pathogenesis of HIV-associated cardiomyopathy. Ann N Y Acad Sci. 2001 Nov;946:57–81. PubMed Europe PMC Scholia
  22. Wu X, Deng Y. Bax and BH3-domain-only proteins in p53-mediated apoptosis. Front Biosci. 2002 Jan 1;7:d151-6. PubMed Europe PMC Scholia
  23. Twu C, Liu NQ, Popik W, Bukrinsky M, Sayre J, Roberts J, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14386–91. PubMed Europe PMC Scholia
  24. Calandria C, Irurzun A, Barco A, Carrasco L. Individual expression of poliovirus 2Apro and 3Cpro induces activation of caspase-3 and PARP cleavage in HeLa cells. Virus Res. 2004 Aug;104(1):39–49. PubMed Europe PMC Scholia
  25. Fiala M, Popik W, Qiao J-H, Lossinsky AS, Alce T, Tran K, et al. HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. Cardiovasc Toxicol. 2004;4(2):97–107. PubMed Europe PMC Scholia
  26. Afanasyeva M, Georgakopoulos D, Rose NR. Autoimmune myocarditis: cellular mediators of cardiac dysfunction. Autoimmun Rev. 2004 Nov;3(7–8):476–86. PubMed Europe PMC Scholia
  27. Holcik M, Sonenberg N. Translational control in stress and apoptosis. Nat Rev Mol Cell Biol. 2005 Apr;6(4):318–27. PubMed Europe PMC Scholia
  28. Marash L, Kimchi A. DAP5 and IRES-mediated translation during programmed cell death. Cell Death Differ. 2005 Jun;12(6):554–62. PubMed Europe PMC Scholia
  29. Barbaro G. HIV-associated cardiomyopathy etiopathogenesis and clinical aspects. Herz. 2005 Sep;30(6):486–92. PubMed Europe PMC Scholia
  30. Yu S-W, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18314–9. PubMed Europe PMC Scholia
  31. Chau DHW, Yuan J, Zhang H, Cheung P, Lim T, Liu Z, et al. Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1. Apoptosis. 2007 Mar;12(3):513–24. PubMed Europe PMC Scholia
  32. Esfandiarei M, McManus BM. Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol. 2008;3:127–55. PubMed Europe PMC Scholia
  33. Knowlton KU. CVB infection and mechanisms of viral cardiomyopathy. Curr Top Microbiol Immunol. 2008;323:315–35. PubMed Europe PMC Scholia
  34. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009 Oct;10(10):1073–80. PubMed Europe PMC Scholia
  35. Blyszczuk P, Kania G, Dieterle T, Marty RR, Valaperti A, Berthonneche C, et al. Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ Res. 2009 Oct 23;105(9):912–20. PubMed Europe PMC Scholia
  36. Kania G, Blyszczuk P, Eriksson U. Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovasc Med. 2009 Nov;19(8):247–52. PubMed Europe PMC Scholia
  37. Vařecha M, Potěšilová M, Matula P, Kozubek M. Endonuclease G interacts with histone H2B and DNA topoisomerase II alpha during apoptosis. Mol Cell Biochem. 2012 Apr;363(1–2):301–7. PubMed Europe PMC Scholia
  38. Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. 2014 Jun;1319(1):82–95. PubMed Europe PMC Scholia
  39. Tschöpe C, Müller I, Xia Y, Savvatis K, Pappritz K, Pinkert S, et al. NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis. Circ Heart Fail. 2017 Sep;10(9):e003870. PubMed Europe PMC Scholia