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Abstract

Coxsackievirus B3 (CVB3) infection can trigger myocarditis and can ultimately lead to dilated cardiomyopathy. It is known that CVB3-induced T-cell infiltration into cardiac tissues is one of the pathological factors causing cardiomyocyte injury by inflammation. However, the underlying mechanism for this remains unclear. We investigated the mechanism of T-cell infiltration by two types of CVB3: the H3 WT strain and the YYFF attenuated strain. T-cell activation was confirmed by changes in the distribution of lymphocyte function-associated antigen-1 (LFA-1). Finally, we identified which viral gene was responsible for LFA-1 activation. CVB3 could infect and activate T-cells and , and activated T-cells were detected in CVB3-infected mouse hearts. LFA-1 expressed on the surface of these T-cells had been activated through the cAMP/Rap1 pathway. Recombinant lentiviruses expressing VP2 of CVB3 could also induce LFA-1 activation via an increase in cAMP, whilst VP2 of YYFF did not. These results indicated that CVB3 infection increased cAMP levels and then activated Rap1 in T-cells. In particular, VP2, among the CVB3 proteins, might be critical for this activation. This VP2–cAMP–Rap1–LFA-1 axis could be a potential therapeutic target for treating CVB3-induced myocarditis.

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2014-09-01
2021-03-05
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References

  1. Aloisi F., Ria F., Adorini L. 2000; Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 21:141–147 [CrossRef][PubMed]
    [Google Scholar]
  2. Alon R., Feigelson S. W. 2012; Chemokine-triggered leukocyte arrest: force-regulated bi-directional integrin activation in quantal adhesive contacts. Curr Opin Cell Biol 24:670–676 [CrossRef][PubMed]
    [Google Scholar]
  3. Cantrell D. 1996; T cell antigen receptor signal transduction pathways. Annu Rev Immunol 14:259–274 [CrossRef][PubMed]
    [Google Scholar]
  4. DiBaise J. K., Zhang H., Crowell M. D., Krajmalnik-Brown R., Decker G. A., Rittmann B. E. 2008; Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 83:460–469 [CrossRef][PubMed]
    [Google Scholar]
  5. Esfandiarei M., McManus B. M. 2008; Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol 3:127–155 [CrossRef][PubMed]
    [Google Scholar]
  6. Fairweather D., Cihakova D. 2009; Alternatively activated macrophages in infection and autoimmunity. J Autoimmun 33:222–230 [CrossRef][PubMed]
    [Google Scholar]
  7. Fortin J. F., Cantin R., Tremblay M. J. 1998; T cells expressing activated LFA-1 are more susceptible to infection with human immunodeficiency virus type 1 particles bearing host-encoded ICAM-1. J Virol 72:2105–2112[PubMed]
    [Google Scholar]
  8. Gebhard J. R., Perry C. M., Harkins S., Lane T., Mena I., Asensio V. C., Campbell I. L., Whitton J. L. 1998; Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol 153:417–428 [CrossRef][PubMed]
    [Google Scholar]
  9. Grabie N., Delfs M. W., Westrich J. R., Love V. A., Stavrakis G., Ahmad F., Seidman C. E., Seidman J. G., Lichtman A. H. 2003; IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis. J Clin Invest 111:671–680 [CrossRef][PubMed]
    [Google Scholar]
  10. Gravanis M. B., Sternby N. H. 1991; Incidence of myocarditis. A 10-year autopsy study from Malmö, Sweden. Arch Pathol Lab Med 115:390–392[PubMed]
    [Google Scholar]
  11. Hashimoto I., Komatsu T. 1978; Myocardial changes after infection with coxsackie virus B3 in nude mice. Br J Exp Pathol 59:13–20[PubMed]
    [Google Scholar]
  12. Henke A., Jarasch N., Martin U., Wegert J., Wildner A., Zell R., Wutzler P. 2008; Recombinant coxsackievirus vectors for prevention and therapy of virus-induced heart disease. Int J Med Microbiol 298:127–134 [CrossRef][PubMed]
    [Google Scholar]
  13. Hioe C. E., Chien P. C. Jr, Lu C., Springer T. A., Wang X. H., Bandres J., Tuen M. 2001; LFA-1 expression on target cells promotes human immunodeficiency virus type 1 infection and transmission. J Virol 75:1077–1082 [CrossRef][PubMed]
    [Google Scholar]
  14. Huber S. A., Sartini D., Exley M. 2002; Vγ4+ T cells promote autoimmune CD8+ cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4+ Th1 cells. J Virol 76:10785–10790 [CrossRef][PubMed]
    [Google Scholar]
  15. Katagiri K., Hattori M., Minato N., Irie S., Takatsu K., Kinashi T. 2000; Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol 20:1956–1969 [CrossRef][PubMed]
    [Google Scholar]
  16. Kim D. S., Nam J. H. 2010; Characterization of attenuated coxsackievirus B3 strains and prospects of their application as live-attenuated vaccines. Expert Opin Biol Ther 10:179–190 [CrossRef][PubMed]
    [Google Scholar]
  17. Kim K. S., Hufnagel G., Chapman N. M., Tracy S. 2001; The group B coxsackieviruses and myocarditis. Rev Med Virol 11:355–368 [CrossRef][PubMed]
    [Google Scholar]
  18. Kim S. M., Park J. H., Chung S. K., Kim J. Y., Hwang H. Y., Chung K. C., Jo I., Park S. I., Nam J. H. 2004; Coxsackievirus B3 infection induces cyr61 activation via JNK to mediate cell death. J Virol 78:13479–13488 [CrossRef][PubMed]
    [Google Scholar]
  19. Kim D. S., Cho Y. J., Kim B. G., Lee S. H., Nam J. H. 2010; Systematic analysis of attenuated coxsackievirus expressing a foreign gene as a viral vaccine vector. Vaccine 28:1234–1240 [CrossRef][PubMed]
    [Google Scholar]
  20. Kim D. S., Park J. H., Kim J. Y., Kim D., Nam J. H. 2012; A mechanism of immunoreceptor tyrosine-based activation motif (ITAM)-like sequences in the capsid protein VP2 in viral growth and pathogenesis of coxsackievirus B3. Virus Genes 44:176–182 [CrossRef][PubMed]
    [Google Scholar]
  21. Kim J. H., Seok H., Lim B. K. 2013; Cardiac-specific coxsackievirus and adenovirus receptor (CAR) deletion inhibit enterovirus infection in murine heart. J Bacteriol Virol 43:210–216 [CrossRef]
    [Google Scholar]
  22. Knowlton K. U., Jeon E. S., Berkley N., Wessely R., Huber S. 1996; A mutation in the puff region of VP2 attenuates the myocarditic phenotype of an infectious cDNA of the Woodruff variant of coxsackievirus B3. J Virol 70:7811–7818[PubMed]
    [Google Scholar]
  23. Lim B. K., Nam J. H., Gil C. O., Yun S. H., Choi J. H., Kim D. K., Jeon E. S. 2005; Coxsackievirus B3 replication is related to activation of the late extracellular signal-regulated kinase (ERK) signal. Virus Res 113:153–157 [CrossRef][PubMed]
    [Google Scholar]
  24. Liu P., Aitken K., Kong Y. Y., Opavsky M. A., Martino T., Dawood F., Wen W. H., Kozieradzki I., Bachmaier K.other authors 2000; The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat Med 6:429–434 [CrossRef][PubMed]
    [Google Scholar]
  25. Luo J., Li C., Xu T., Liu W., Ba X., Wang X., Zeng X. 2014; PI3K is involved in β1 integrin clustering by PSGL-1 and promotes β1 integrin-mediated Jurkat cell adhesion to fibronectin. Mol Cell Biochem 385:287–295 [CrossRef][PubMed]
    [Google Scholar]
  26. Malbec M., Roesch F., Schwartz O. 2011; A new role for the HTLV-1 p8 protein: increasing intercellular conduits and viral cell-to-cell transmission. Viruses 3:254–259 [CrossRef][PubMed]
    [Google Scholar]
  27. Marlin S. D., Springer T. A. 1987; Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51:813–819 [CrossRef][PubMed]
    [Google Scholar]
  28. Mena I., Perry C. M., Harkins S., Rodriguez F., Gebhard J., Whitton J. L. 1999; The role of B lymphocytes in coxsackievirus B3 infection. Am J Pathol 155:1205–1215 [CrossRef][PubMed]
    [Google Scholar]
  29. Mor A., Dustin M. L., Philips M. R. 2007; Small GTPases and LFA-1 reciprocally modulate adhesion and signaling. Immunol Rev 218:114–125 [CrossRef][PubMed]
    [Google Scholar]
  30. Park J. H., Kim D. S., Cho Y. J., Kim Y. J., Jeong S. Y., Lee S. M., Cho S. J., Yun C. W., Jo I., Nam J. H. 2009; Attenuation of coxsackievirus B3 by VP2 mutation and its application as a vaccine against virus-induced myocarditis and pancreatitis. Vaccine 27:1974–1983 [CrossRef][PubMed]
    [Google Scholar]
  31. Pyszniak A. M., Welder C. A., Takei F. 1994; Cell surface distribution of high-avidity LFA-1 detected by soluble ICAM-1-coated microspheres. J Immunol 152:5241–5249[PubMed]
    [Google Scholar]
  32. Roossien F. F., de Rijk D., Bikker A., Roos E. 1989; Involvement of LFA-1 in lymphoma invasion and metastasis demonstrated with LFA-1-deficient mutants. J Cell Biol 108:1979–1985 [CrossRef][PubMed]
    [Google Scholar]
  33. Rovira-Clavé X., Angulo-Ibáñez M., Reina M., Espel E. 2014; The PDZ-binding domain of syndecan-2 inhibits LFA-1 high-affinity conformation. Cell Signal 26:1489–1499 [CrossRef][PubMed]
    [Google Scholar]
  34. Russell R. A., Martin N., Mitar I., Jones E., Sattentau Q. J. 2013; Multiple proviral integration events after virological synapse-mediated HIV-1 spread. Virology 443:143–149 [CrossRef][PubMed]
    [Google Scholar]
  35. Salas A., Shimaoka M., Phan U., Kim M., Springer T. A. 2006; Transition from rolling to firm adhesion can be mimicked by extension of integrin αLβ2 in an intermediate affinity state. J Biol Chem 281:10876–10882 [CrossRef][PubMed]
    [Google Scholar]
  36. Shamri R., Grabovsky V., Gauguet J. M., Feigelson S., Manevich E., Kolanus W., Robinson M. K., Staunton D. E., von Andrian U. H., Alon R. 2005; Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat Immunol 6:497–506 [CrossRef][PubMed]
    [Google Scholar]
  37. Simonson W. T., Franco S. J., Huttenlocher A. 2006; Talin1 regulates TCR-mediated LFA-1 function. J Immunol 177:7707–7714 [CrossRef][PubMed]
    [Google Scholar]
  38. Stanley P., Smith A., McDowall A., Nicol A., Zicha D., Hogg N. 2008; Intermediate-affinity LFA-1 binds α-actinin-1 to control migration at the leading edge of the T cell. EMBO J 27:62–75 [CrossRef][PubMed]
    [Google Scholar]
  39. Stanley P., Tooze S., Hogg N. 2012; A role for Rap2 in recycling the extended conformation of LFA-1 during T cell migration. Biol Open 1:1161–1168 [CrossRef][PubMed]
    [Google Scholar]
  40. Steinman L. 2007; A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145 [CrossRef][PubMed]
    [Google Scholar]
  41. Tracy S., Höfling K., Pirruccello S., Lane P. H., Reyna S. M., Gauntt C. J. 2000; Group B coxsackievirus myocarditis and pancreatitis: connection between viral virulence phenotypes in mice. J Med Virol 62:70–81 [CrossRef][PubMed]
    [Google Scholar]
  42. Veillette A., Bookman M. A., Horak E. M., Samelson L. E., Bolen J. B. 1989; Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature 338:257–259 [CrossRef][PubMed]
    [Google Scholar]
  43. Yndestad A., Holm A. M., Müller F., Simonsen S., Frøland S. S., Gullestad L., Aukrust P. 2003; Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovasc Res 60:141–146 [CrossRef][PubMed]
    [Google Scholar]
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