1887

Chapter 32 : Pathogenesis of Coxsackievirus В Infections

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Pathogenesis of Coxsackievirus В Infections, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817916/9781555812102_Chap32-1.gif /docserver/preview/fulltext/10.1128/9781555817916/9781555812102_Chap32-2.gif

Abstract:

Regarding the pathogenesis of enteroviral heart disease there has been uncertainty whether viral cytotoxicity or immune-mediated processes are crucial for organ pathology during acute and persistent heart muscle infection. This chapter provides experimental evidence for the decisive role of virus replication in the induction and maintenance of chronic myocardial damage. In addition, the capacity of cellular signal transduction pathways to modulate enterovirus replication as well as coxsackieviruses of group B (CVB) receptor interactions and their role in pathogenesis are discussed. It has been found that in all investigated mouse strains CVB3 is capable of inducing acute myocarditis, which is characterized by virus-induced myocytolysis and reactive formation of interstitial mononuclear infiltrates. Importantly, persistent infection of myocytes was found to be related with morphological changes of the myofibrils. Preferential targets of the enteroviral proteinase 2A are proteins involved in the Cap-dependent translation of cellular mRNAs, since enteroviruses employ a Cap-independent mechanism of protein translation. Importantly, recognition of cellular targets by viral proteinases may be preceded by virus-induced modifications of these proteins. As recently suggested for infections with encephalomyocarditis virus, activation of p38/MAPK could be induced by the dsRNA intermediates during enteroviral replication.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32

Key Concept Ranking

Cell-Mediated Immune Response
0.43987155
Viral RNA
0.40722677
0.43987155
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Detection of CVB3 RNA in the myocardium of immunocompetent mice (A) 3 days, (B) 6 days, (C) 12 days, and (D) 30 days pi. At any stage of the disease viral RNA is clearly localized to myocytes as detected by radioactive in situ hybridization. In spleens of acutely infected animals, CVB3 RNA-positive cells were primarily observed (E) in the white pulp of follicles whereas at later stages of the infection virus RNA was detected (F) in immune cells within the germinal center.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Visualization of CVB3 RNA in murine heart muscles by electron microscopic in situ hybridization in the course of virus replication. Following (A) viremia, replicative minus-strand CVB3 RNA was detected (B) in myocytes in close association with sarcoplasmic reticulum. Genomic viral RNA was observed in (C, D) vesiculated regions and (E) virus-induced vacuoles of myocytes. (F) At later stages of acute virus replication viral RNA was found to be related with histopathologic findings typical for myocyte necrosis.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Differencial interactions of CVB3 variants with host cells. (A) CVB3 and CVB3-HA differ in their interaction with CAR (46 kDa) and DAF (70 kDa). (B) Plaque phenotypes of CVB3 and CVB3-HA on CAR- and DAF-expressing HeLa cells. (C) Growth curves of CVB3 and CVB3-HA in HeLa, CHO, CHOCAR, and CHODAF cells. Despite clear differences in their binding phenotypes and plaque sizes, both CVB3 variants exhibit comparable 12-h growth curves.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

In situ detection of CVB3 and virus-induced signaling pathways in murine heart muscle. A.BY/SnJ mice were intraperitoneally infected with CVB3 or CVB3-HA (10 PFU) and hearts were analyzed 8 days pi. Differences in the cardiotropism of CVB3 and CVB3-HA are demonstrated by in situ hybridization using a S-labeled enterovirus-specific probe ( ). Immunohistochemical staining of serial myocardial tissue sections with phospho-ERK/MAPK- and phospho-JNK/SAPK-specific antibodies reveals a close spatial correlation of ERK/MAPK expression and viral replication.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5
FIGURE 5

Virus-induced activation of МАРК signaling pathways. CVB3- or CVB3-HA-infected (0 to 6 h pi) HeLa cells were subjected to Western blotting using antibodies specific for the phosphorylated forms of JNK/SAPK, ERK/MAPK, and p38/MAPK. Early activation of the proapoptotic JNK/SAPK pathway is temporally followed by activation of the antiapoptotic ERK/ МАРK pathway.

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817916.chap32
1. Agol, V. I.,, G. A. Belov,, K. Bienz,, D. Egger,, M. S. Kolesnikova,, L. I. Romanova,, L. V. Sladkova,, and E. A. Tolskaya. 2000. Competing death programs in poliovirus-infected cells: commitment switch in the middle of the infectious cycle. J. Virol. 74:55345541.
2. Anderson, D.,, J. E. Wilson,, C. M. Carthy,, S. Yang,, R. Kandolf,, and B. M. McManus. 1996. Direct interaction of coxsackievirus B3 with immune cells in the splenic compartment of mice susceptible or resistant to myocarditis. J. Virol. 70:46324645.
3. Badorff, C.,, N. Berkely,, S. Mehrotra,, J. W. Talhouk,, R. E. Rhoads,, and K. U. Knowlton. 2000. Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue. J. Biol. Chem. 275:1119111197.
4. Badorff, C.,, L. Gil-Hwan,, B. J. Lamphear,, M. E. Martone,, K. P. Campbell,, R. E. Rhoads,, and K. U. Knowlton. 1999. Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat. Med. 5:320326.
5. Bergelson, J. M.,, J. A. Cunningham,, G. Droguett,, E. A Kurt-Jones,, A. Krithivas,, J. S Hong,, M. S Horwitz,, R. L. Crowell,, and R. W. Finberg. 1997. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275:13201323.
6. Bergelson, J. M.,, J. G. Mohanty,, R. L. Crowell,, N. F. St. John,, D. M. Lublin,, and R. W. Finberg. 1995. Coxsackievirus B3 adapted to growth in RD cells binds to decay-accelerating factor (CD55). J. Virol. 69:19031906.
7. Bossy-Wetzel, E.,, L. Bakiri,, and M. Yaniv. 1997. Induction of apoptosis by the transcription factor c-Jun. EMBO J. 16:16951709.
8. Brader, J. T.,, and I. Kovesdi. 1997. Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J. Virol. 71:398404.
9. Carthy, C. M.,, D. J. Granville,, K. A. Watson,, D. R. Anderson,, J. E. Wilson,, D. Yang,, D. W. Hunt,, and B. M. McManus. 1998. Caspase activation and specific cleavage of substrates after coxsackievirus B3-induced cytopathic effect in HeLa cells. J. Virol. 72:76697675.
10. Chow, L. H.,, K. W. Beisel,, and B. M. McManus. 1992. Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab. Invest. 66:2431.
11. Fenton, M.,, and A. J. Sinclair. 1999. Divergent requirements for the MAPK/ERK signal transduction pathway during initial vims infection of quiescent primary B cells and disruption of Epstain-Barr virus latency by phorbol esters. J. Virol. 73:89138916.
12. Foulis, A. K.,, M. A. Farquharson,, S. O. Cameron,, M. McGill,, H. Schönke,, and R. Kandolf. 1990. A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with type 1 (insulin-dependent) diabetes and pancreases and hearts of infants who died of coxsackie viral myocarditis. Diabetologia 33:290298.
13. Franz, W. M.,, D. Breves,, K. Klingel,, G. Brem,, P. H. Hof Schneider,, and R. Kandolf. 1993. Heart-specific targeting of firefly luciferase by myosin-light-chain-2 promoter and developmental regulation in transgenic mice. Circ. Res. 73:629638.
14. Hirasawa, K.,, H. S. Jun,, H. S. Han,, M. L. Zhang,, M. D. Hollenberg,, and J. W. Yoon. 1999. Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppresssion of nitric oxide production in macrophages. J. Virol. 73:85418548.
15. Huber, M.,, H.-C. Selinka,, and R. Kandolf. 1997. Tyrosine phosphorylation events during coxsackievirus B3 replication. J. Virol. 71:595600.
16. Huber, M.,, K. A. Watson,, H.-C. Selinka,, C. M. Carthy,, K. Klingel,, B. M. McManus,, and R. Kandolf. 1999. Cleavage of RasGAP and phosphorylation of mitogen-activated protein kinase in the course of coxsackievirus B3 replication. J. Virol. 73:35873594.
17. Huttunen, R.,, J. Heino,, and T. Hyypiá. 1997. Echovirus 1 replication, not only virus binding to its receptor, VLA-2, is required for the induction of cellular immediate-early genes. J. Virol. 71:41764180.
18. Huttunen, P.,, T. Hyypiá,, P. Vihinen,, L. Nissinen,, and J. Heino. 1998. Echovirus 1 infection induces both stressand growth-activated mitogen-activated protein kinase pathways and regulates the transcription of cellular immediate-early genes. Virology 250:8593.
19. Iordanov, M. S.,, J. M. Paranjape,, A. Zhou,, J. Wong,, B. R. Williams,, E. F. Meurs,, R. H. Silverman,, and B. E. Magun. 2000. Activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase by double-stranded RNA and encephalomyocarditis virus: involvement of Rnase L, protein kinase R, and alternative pathways. Mol. Cell. Biol. 20:617627.
20. Joachims, M.,, P. C. van Breugel,, and R. E. Lloyd. 1999. Cleavage of poly(A)-binding protein by enterovirus proteases concurrent with inhibition of translation in vitro. J. Virol. 73:718727.
21. Kandolf, R.,, D. Ameis,, P. Kirschner,, A. Canu,, and P. H. Hofschneider. 1987. in situ detection of enteroviral genomes in myocardial cells by nucleic acid hybridization: an approach to the diagnosis of viral heart disease. Proc. Natl. Acad. Sci. USA 84:62726276.
22. Kandolf, R.,, and P. H. Hofschneider. 1985. Molecular cloning of the genome of a cardiotropic coxsackie B3 virus: full-length reverse-transcribed recombinant cDNA generates infectious virus in mammalian cells. Proc. Natl. Acad. Sci. USA 82:48184822.
23. Kandolf, R.,, K. Klingel,, R. Zell,, H.-C. Selinka,, U. Raab,, W. Schneider-Brachert,, and B. Bultmann. 1993. Molecular pathogenesis of enterovirus-induced myocarditis: virus persistence and chronic inflammation. InterVirology 35: 140151.
24.. Kandolf, R.,, M. Sauter,, C. Aepinus,, J.-J. Schnorr,, H.-C. Selinka,, and K. Klingel. 1999. Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system. Virus Res. 62:149158.
25. Kerekatte, V.,, B. D. Keiper,, C. Badorff,, A. Cai,, K. U. Knowlton,, and R. E. Rhoads. 1999. Cleavage of poly(A)-binding protein by coxsackievirus 2A protease in vitro and in vivo: another mechanism for host protein synthesis shutoff. J. Virol. 73:709717.
26. Klingel, K.,, C. Hohenadl,, A. Canu,, M. Albrecht,, M. Seemann,, G. Mall,, and R. Kandolf. 1992. Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage and inflammation. Proc. Natl. Acad. Sci. USA 89:314318.
27. Klingel, K.,, and R. Kandolf. 1993. The role of enterovirus replication in the development of acute and chronic heart muscle disease in different immunocompetent mouse strains. Scand. J. Infect. Dis. Suppl. 88:7985.
28. Klingel, K.,, P. Rieger,, G. Mall,, H.-C. Selinka,, M. Huber,, and R. Kandolf. 1998. Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects. Lab. Invest. 78:12271237.
29. Klingel, K.,, S. Stephan,, M. Sauter,, R. Zell,, B. M. McManus,, B. Bültmann,, and R. Kandolf. 1996. Pathogenesis of murine enterovirus myocarditis: virus dissemination and immune cell targets. J. Virol. 70:88888895.
30. Klump, W. M.,, I. Bergmann,, B. C. Muller,, D. Ameis,, and R. Kandolf. 1990. Complete nucleotide sequence of infectious coxsackievirus B3 cDNA: two initial 5'uridine residues are regained during plus-strand RNA synthesis. J. Virol. 64:15731583.
31. Lamphear, B. J.,, R. Yan,, R. Yang,, D. Waters,, H. D. Liebig,, H. Klump,, E. Kuechler,, T. Skern,, and R. E. Rhoads. 1993. Mapping the cleavage site in protein synthesis initiation factor eIF-4 gamma of the 2A proteases from human coxsackievirus and rhinovirus. J. Biol. Chem. 268:1920019203.
32. Lee, K. J.,, R. S. Ross,, H. A. Rockman,, A. N. Harris,, T. X. O'Brien,, M. van Bilsen,, H. E. Shubeita,, R. Kandolf,, G. Brem,, J. Price,, S. M. Evans,, H. Zhu,, W. M. Franz,, and K. R. Chien. 1992. Myosin light chain-2 luciferase transgenic mice reveal distinct regulatory programs for cardiac and skeletal muscle-specific expression of a single contractile protein gene. J. Biol. Chem. 267: 1587515885.
33. Martin, P.,, W. C. Vass,, J. T. Schiller,, D. R. Lowry,, and T. J. Velu. 1989. The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors. Cell 59:2132.
34. Martino, T.,, P. Liu,, and M. J. Sole. 1994- Viral infection and the pathogenesis of dilated cardiomyopathy. Circ. Res. 74:182188.
35. McManus, B. M.,, and R. Kandolf. 1991. Evolving concepts of cause, consequence, and control in myocarditis. Curr. Opin. Cardiol. 6:418427.
36. Muir, P.,, U. Kámmerer,, K. Korn,, M. N. Mulders,, T. Pöyry,, B. Weissbrich,, R. Kandolf,, G. M. Cleator,, and A. M. van Loon. 1998. Molecular typing of enteroviruses: current status and future requirements. Clin. Microbiol. Rev. 11:202227.
37. Pasch, A.,, J.-H. Küpper,, A. Wolde,, R. Kandolf,, and H.-C. Selinka. 1999. Comparative analysis of virus-host cell interactions of haemagglutinating and non-haemagglutinating strains of coxsackievirus B3. J. Gen. Virol. 80:31533158.
38. Sato, S.,, R. Tsutsumi,, A. Burke,, G. Calson,, V. Porro,, Y. Seko,, K. Okumura,, R. Kawana,, and R. Virmani. 1994. Persistence of replicating coxsackievirus B3 in the athymic murine heart is associated with development of myocarditic lesions. J. Gen. Virol. 7:29112924.
38.a. Selinka, H. C.,, A. Wolde,, A. Pasch,, K. Klingel,, J. J. Schnorr,, J. H. Küpper,, A. M. Lindberg,, and R. Kandolf. 2002. Comparative analysis of two coxsackievirus B3 strains: putative influence of virus-receptor interactions on pathogenesis. J. Med. Virol. 67:224233.
39. Shafren, D. R.,, D. T. Williams,, and R. D. Barry. 1997. A decay-accelerating factor-binding strain of coxsackievirus B3 requires the coxsackievirus-adenovirus receptor protein to mediate lytic infection of rhabdomyosarcoma cells. J. Virol. 71:98449848.
40. Tam, P. E.,, and R. P. Messner. 1999. Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution. J. Virol. 73:1011310121.
41. Tomko, R. P.,, R. Xu,, and L. Philipson. 1997. HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Natl. Acad. Sci. USA 94:33523356.
42. Wessely, R.,, A. Henke,, R. Zeil,, R. Kandolf,, and K. U. Knowlton. 1998. Low-level expression of a mutant cox-sackieviral cDNA induces a myocytopathic effect in culture: an approach to the study of enteroviral persistence in cardiac myocytes. Circulation 98:450457.
43. Wessely, R.,, K. Klingel,, L. F. Santana,, N. Dalton,, M. Hongo,, W. J. Lederer,, R. Kandolf,, and K. U. Knowlton. 1998. Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy. J. Clin. Invest. 102:14441453.
44. Xia, Z.,, M. Dickens,, J. Raingeaud,, R. J. Davis,, and M. E. Greenberg. 1995. Opposing effects of ERK and JNK-p38 MAP kinase on apoptosis. Science 270:13261331.

Tables

Generic image for table
TABLE 1

Cleavage of host cell proteins by coxsackieviral proteinases 2A, 3C, and 3CD

Citation: Kandolf R, Selinka H, Klingel K. 2002. Pathogenesis of Coxsackievirus В Infections, p 405-413. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch32

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error