title: Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization.
abstract: Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, affects about 5-20% of the world population and lacks efficient treatments. We previously reported that monocyte chemotactic protein-1 (MCP-1, CCL2) was significantly induced during CVB3 infection and greatly contributed to the myocardic inflammation and injury. Herein a CCL2 mutant with removed chemotactic activity was administrated and its therapeutic effect on CVB3-induced myocarditis was explored. A dominant negative CCL2 mutant, lacking the N-terminal amino acids 2-8 (CCL2(Δ2-8)), was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection, severity of myocarditis was evaluated by weight loss, survival rate, serological indices and pathological observation. Systemic and local Th1/Th2 cytokine profiles were also assessed. Mice receiving pCCL2(Δ2-8) exhibited a profound attenuation of myocarditis compared to pcDNA3.1 or non-treated mice, as evidenced by invariant body weight, decreased serum CK-MB level, reduced myocardial inflammatory infiltration and increased survival. This effect was not attributable to the efficient viral clearance, but associated with weakened Th1 immune responses, as evidenced by significantly reduced CD4(+)IFN-γ(+) T cell frequency and Th1 cytokine level systemically and locally. Strategy of blocking in vivo CCL2 activity could effectively alleviate the severity of CVB3-induced myocarditis and may present an alternative therapeutic approach against viral myocarditis.
authors.affiliation: Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou 215123, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yue
authors.forename: Jun
authors.initials: J
authors.lastname: Gui
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D003384:Coxsackievirus Infections; D004770:Enterovirus / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D009205:Myocarditis / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy / Q000821:virology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D050505:Mutant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma