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TcVac3 induced control of Trypanosoma cruzi infection and chronic myocarditis in mice
Shivali Gupta1, Nisha Jain Garg
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
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.
Insights
A DNA-prime/MVA-boost vaccine (TcVac3) generated strong T cell immunity, controlling Trypanosoma cruzi infection by over 92% and preventing chronic inflammation and heart damage in mice.
Area of Science:
- Immunology
- Vaccinology
- Parasitology
Background:
- Trypanosoma cruzi (Tc) infection causes Chagas disease, a significant global health concern.
- Effective vaccines are needed to control Tc infection and prevent its chronic, pathological manifestations.
- Previous studies identified TcG2 and TcG4 antigens recognized by host immune responses.
Purpose of the Study:
- To characterize the immune responses elicited by the TcVac3 DNA-prime/MVA-boost vaccine against Trypanosoma cruzi.
- To evaluate the vaccine's efficacy in controlling Tc infection and preventing chronic pathology.
- To assess the role of cytokine adjuvants (IL-12 and GMCSF) in vaccine-induced protection.
Main Methods:
- Mice were immunized with TcVac3, followed by challenge infection with T. cruzi.
- Immune responses, including antibody production, T cell cytokine profiles, and cytolytic effector function, were analyzed.
- Parasite load, tissue inflammation, and fibrosis were assessed in vaccinated and control mice during the chronic phase.
Main Results:
- TcVac3 induced strong antigen-specific, high-avidity antibodies (IgG2b>IgG1) and robust Tc-specific CD8(+) T cell responses with a type-1 cytokine and cytolytic effector phenotype.
- Vaccine-induced effector T cells expanded upon challenge, providing >92% control of T. cruzi infection.
- IL-12 and GMCSF adjuvants did not enhance vaccine-induced resistance. Vaccinated mice showed reduced chronic inflammation, tissue parasitism, and fibrosis, with a shift towards immunoregulatory T cells.
Conclusions:
- TcVac3 elicits potent type-1 effector T cell immunity that effectively controls T. cruzi infection.
- The vaccine prevents chronic inflammation and myocarditis in chagasic mice by promoting a shift towards anti-inflammatory responses post-infection.
- TcVac3 represents a promising candidate for Chagas disease prevention.
