Delivery of antigenic candidates by a DNA/MVA heterologous approach elicits effector CD8(+)T cell mediated immunity against Trypanosoma cruzi.
In this study, we have characterized the immune mechanisms elicited by antigenic candidates, TcG2 and TcG4, delivered by a DNA-prime/MVA-boost approach, and evaluated the host responses to Trypanosoma cruzi infection in C57BL/6 mice. Immunization of mice with antigenic candidates elicited antigen-specific, high-avidity, trypanolytic antibody response (IgG2b>IgG1) and CD8(+)T cells that exhibited type-1 cytolytic effector (CD8(+)CD107a(+)IFN-γ(+)Perforin(+)) phenotype. The extent of TcG2-dependent type 1 B and T cell immunity was higher than that noted in TcG4-immunized mice, and expanded accordingly in response to challenge infection with T. cruzi. The progression of chronic phase in immunized mice was associated with persistence of IgGs, 55-90% reduction in the frequency of proinflammatory (IFN-γ(+) or TNF-α(+)) CD8(+)T cells, and an increase or emergence of immunoregulatory (IL-10(+)) CD4/CD8 T cells. The tissue parasitism, infiltration of inflammatory infiltrate, parasite persistence, and fibrosis were decreased by 82-92% in heart and skeletal muscle of immunized/chronically infected mice. Control mice exhibited a significantly low antibody response, consistent activation of effector CD8(+)T cells dominated by pro-inflammatory phenotype and mixed cytokine profile (IFN-γ+TNF-α>IL-4+IL-10), parasite persistence and pathologic damage in chagasic hearts. We conclude that delivery of TcG2 or TcG4 by DNA-rMVA approach elicits effective antibody and CD8(+)T cell mediated immunity against T. cruzi and Chagas disease. The emergence of type 2 cytokine and T cell response in chronic phase was indicative of prevention of clinical disease.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, United States.
Shivali
S
Gupta
Nisha Jain
NJ
Garg
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D005822:Genetic Vectors; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004337:Drug Carriers; D007074:Immunoglobulin G; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic