title: Coxsackievirus B3 regulates T-cell infiltration into the heart by lymphocyte function-associated antigen-1 activation via the cAMP/Rap1 axis.
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 in vivo and in vitro, 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.
authors.affiliation: Department of Biotechnology, Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Shim
authors.affiliation: Department of Biotechnology, Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Dae-Sun
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Whajung
authors.initials: W
authors.lastname: Cho
authors.affiliation: Department of Biotechnology, Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Nam
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000276:immunology / Q000821:virology; D003384:Coxsackievirus Infections / Q000276:immunology / Q000821:virology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D004770:Enterovirus / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006321:Heart / Q000821:virology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000276:immunology / Q000821:virology; D009206:Myocardium / Q000166:cytology / Q000276:immunology; D011991:Receptors, Virus / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D020827:rap1 GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C573420:ICAM1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D011991:Receptors, Virus; C105941:coxsackievirus B receptor; D018799:Intercellular Adhesion Molecule-1; D000242:Cyclic AMP; D020827:rap1 GTP-Binding Proteins