title: CXCL10 inhibits viral replication through recruitment of natural killer cells in coxsackievirus B3-induced myocarditis.
abstract: Coxsackievirus (CV)B3 is the primary cause of viral myocarditis. We previously observed CXC chemokine ligand 10 (CXCL10) upregulation in the myocardium early in infection. However, the impact of CXCL10 in CVB3-induced myocarditis is unknown. Using isolated primary mouse cardiomyocytes we demonstrated for the first time that cardiomyocytes can express CXCL10 on interferon-gamma stimulation. To explore the role of CXCL10 in CVB3-induced myocarditis, both CXCL10 transgenic and knockout mice were used. Following CVB3 challenges, the viral titer in the hearts inversely correlated with the levels of CXCL10 at early phase of infection before visible immune infiltration. Furthermore, as compared with the control mice, the decreased virus titers in the CXCL10 transgenic mouse hearts led to less cardiac damage and better cardiac function and vice verse in the knockout mice. This antiviral ability of CXCL10 might be through recruitment of natural killer (NK) cells to the heart and increased interferon-gamma expression early in infection. At day 7 postinfection, with massive influx of mononuclear cells the expression of CXCL10 enhanced the infiltration of CXCR3(+) cells, CD4(+), and CD8(+) T cells, as well as the expression of associated inflammatory cytokines. However, the augmented accumulation of these immune cells and associated cytokines failed to alter the viral clearance and mice survival. These results suggest the protective role of CXCL10 during the early course of CVB3 infection, which is attributed to the recruitment of NK cells. Nonetheless, CXCL10-directed chemoattractant effect is not sufficient for host to clear the virus in the heart.
authors.affiliation: Department of Pathology and Laboratory Medicine, The iCAPTURE Center, University of British Columbia, St Paul's Hospital, Vancouver, BC, Canada.
authors.forename: Ji
authors.initials: J
authors.lastname: Yuan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Travis
authors.initials: T
authors.lastname: Lim
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianqing
authors.initials: J
authors.lastname: He
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Walker
authors.forename: Courtney
authors.initials: C
authors.lastname: Shier
authors.forename: Yinjing
authors.initials: Y
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Su
authors.forename: Alhousseynou
authors.initials: A
authors.lastname: Sall
authors.forename: Bruce
authors.initials: B
authors.lastname: McManus
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D003384:Coxsackievirus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D004770:Enterovirus / Q000472:pathogenicity*; D007249:Inflammation / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D013997:Time Factors; D014779:Virus Replication
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D016753:Interleukin-10; D007371:Interferon-gamma