title: TcVac3 induced control of Trypanosoma cruzi infection and chronic myocarditis in mice.
abstract: We characterized the immune responses elicited by a DNA-prime/MVA-boost vaccine (TcVac3) constituted of antigenic candidates (TcG2 and TcG4), shown to be recognized by B and T cell responses in Trypanosoma cruzi (Tc) infected multiple hosts. C57BL/6 mice immunized with TcVac3 elicited a strong antigen-specific, high-avidity, trypanolytic antibody response (IgG2b>IgG1); and a robust antigen- and Tc-specific CD8(+)T cell response with type-1 cytokine (IFN-γ(+)TNF-α>IL-4(+)IL-10) and cytolytic effector (CD8(+)CD107a(+)IFN-γ(+)Perforin(+)) phenotype. The vaccine-induced effector T cells significantly expanded upon challenge infection and provided >92% control of T. cruzi. Co-delivery of IL-12 and GMCSF cytokine adjuvants didn't enhance the TcVac3-induced resistance to T. cruzi. In chronic phase, vaccinated/infected mice exhibited a significant decline (up to 70%) in IFN-γ(+)CD8(+)T cells, a predominance of immunoregulatory IL-10(+)/CD4(+)T and IL10(+)/CD8(+)T cells, and presented undetectable tissue parasitism, inflammatory infiltrate, and fibrosis in vaccinated/infected mice. In comparison, control mice responded to challenge infection by a low antibody response, mixed cytokine profile, and consistent activation of pro-inflammatory CD8(+)T cells associated with parasite persistence and pathologic damage in the heart. We conclude that TcVac3 elicited type-1 effector T cell immunity that effectively controlled T. cruzi infection, and subsequently, predominance of anti-inflammatory responses prevented chronic inflammation and myocarditis in chagasic mice.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Shivali
authors.initials: S
authors.lastname: Gupta
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000915:Antibody Affinity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002598:Chagas Cardiomyopathy / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002908:Chronic Disease / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007117:Immunization, Secondary; D051379:Mice; D016052:Protozoan Vaccines / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology / Q000502:physiology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D016207:Cytokines; C560489:MVA vaccine; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; D014765:Viral Vaccines
references.citation: Curr Mol Med. 2008 Sep;8(6):510-8
references.pmid: 18781958
references.citation: Science. 2002 Dec 13;298(5601):2199-202
references.pmid: 12481138
references.citation: Infect Immun. 2007 Apr;75(4):1886-94
references.pmid: 17283096
references.citation: J Pathol. 2011 Dec;225(4):583-96
references.pmid: 21952987
references.citation: Immunol Cell Biol. 2003 Apr;81(2):121-9
references.pmid: 12631235
references.citation: Infect Immun. 2004 Nov;72(11):6245-54
references.pmid: 15501750
references.citation: AIDS Res Hum Retroviruses. 2008 Feb;24(2):195-206
references.pmid: 18240957
references.citation: Clin Diagn Lab Immunol. 1998 Nov;5(6):799-803
references.pmid: 9801337
references.citation: Virology. 2007 Sep 15;366(1):84-97
references.pmid: 17499326
references.citation: Vaccine. 2012 Nov 26;30(50):7179-86
references.pmid: 23079191
references.citation: Exp Parasitol. 1981 Jun;51(3):325-34
references.pmid: 6785102
references.citation: J Immunol. 1988 Jun 15;140(12):4342-7
references.pmid: 3131431
references.citation: Braz J Med Biol Res. 2005 Apr;38(4):509-22
references.pmid: 15962176
references.citation: Scand J Immunol. 2000 May;51(5):511-9
references.pmid: 10792844
references.citation: Infect Immun. 1991 May;59(5):1633-8
references.pmid: 1902193
references.citation: Int Microbiol. 2004 Jun;7(2):83-94
references.pmid: 15248156
references.citation: J Leukoc Biol. 2007 Nov;82(5):1027-32
references.pmid: 17615380
references.citation: Clin Diagn Lab Immunol. 2001 Jul;8(4):802-5
references.pmid: 11427430
references.citation: Curr Opin Biotechnol. 2004 Dec;15(6):506-12
references.pmid: 15560976
references.citation: Infect Immun. 2005 Nov;73(11):7356-65
references.pmid: 16239534
references.citation: Front Biosci. 2007 May 01;12:2797-806
references.pmid: 17485260
references.citation: J Clin Invest. 2008 May;118(5):1776-84
references.pmid: 18398511
references.citation: Circulation. 2007 Mar 6;115(9):1109-23
references.pmid: 17339569
references.citation: Clin Vaccine Immunol. 2008 Aug;15(8):1158-64
references.pmid: 18550728
references.citation: Am J Pathol. 2005 Aug;167(2):305-13
references.pmid: 16049318
references.citation: Vaccine. 2006 Apr 5;24(15):3026-34
references.pmid: 16488059
references.citation: Vaccine. 2006 May 29;24(22):4709-15
references.pmid: 16621181
references.citation: Clin Diagn Lab Immunol. 2001 Jan;8(1):112-8
references.pmid: 11139203
references.citation: PLoS Negl Trop Dis. 2011;5(5):e1050
references.pmid: 21625470
references.citation: BMC Res Notes. 2011 Jun 06;4:170
references.pmid: 21645376
references.citation: PLoS Negl Trop Dis. 2010 Aug 10;4(8):e797
references.pmid: 20706586
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Infect Immun. 2009 Oct;77(10):4383-95
references.pmid: 19651871
references.citation: J Infect Dis. 2008 Nov 15;198(10):1482-90
references.pmid: 18808335
references.citation: Trans R Soc Trop Med Hyg. 1993 Mar-Apr;87(2):220-3
references.pmid: 8337734
references.citation: Adv Parasitol. 2011;75:121-46
references.pmid: 21820554
references.citation: Vaccine. 2006 May 22;24(21):4554-61
references.pmid: 16150517
references.citation: Hum Gene Ther. 2004 Sep;15(9):878-86
references.pmid: 15353042
references.citation: Eur J Immunol. 2001 Jan;31(1):265-75
references.pmid: 11265643
references.citation: Biochem J. 2004 Aug 1;381(Pt 3):743-52
references.pmid: 15101819
references.citation: J Infect Dis. 2002 Oct 15;186(8):1065-73
references.pmid: 12355355
references.citation: Infect Immun. 2008 Jan;76(1):324-33
references.pmid: 17967857
references.citation: Infect Immun. 2001 Oct;69(10):6558-63
references.pmid: 11553607
references.citation: Infect Immun. 2004 Sep;72(9):5283-91
references.pmid: 15322024
references.citation: Microbes Infect. 2006 Mar;8(3):598-603
references.pmid: 16427798
references.citation: Vaccine. 2007 Apr 30;25(17):3277-83
references.pmid: 17257714