Journal
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2021.676183
Keywords
rapamycin; mTOR; CD8(+) T-cells; vaccine; Trypanosoma cruzi; effector CD8+T cells; memory CD8+T cells
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2014/19422-5, 2016/02840-4, 2015/08814-2, 2012/22514-3, 2018/15607-1]
- Instituto Nacional de Ciencia e Tecnologia em Vacinas
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
Ask authors/readers for more resources
Deficiency in memory formation and increased immunosenescence are key features of Trypanosoma cruzi infection. A vaccination strategy using a DNA prime and recombinant adenovirus boost has shown efficacy in generating CD8(+) T-cell response against the parasite. Inhibiting mTOR with rapamycin during vaccination enhances CD8(+) T-cell response and improves survival rates in T. cruzi-infected mice, suggesting a potential use of mTOR inhibitor as an adjuvant in vaccine development against intracellular parasites.
Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8(+) T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8(+) T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8(+) T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8(+) T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8(+) T-cells and the percentage of the polyfunctional population, which degranulated (CD107a(+)) and secreted both interferon gamma (IFN gamma) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8(+) T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8(+) T-cell response.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available