Division of Infectious Disease and Immunology, Department of Medicine
Immunopathology | Parasitic Diseases | Parasitology | Pathogenic Microbiology
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 (IFNgamma) 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.
CD8+ T-cells, Trypanosoma cruzi, effector CD8+ T cells, mTOR, memory CD8+ T cells, rapamycin, vaccine
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Copyright © 2021 Moraschi, Noronha, Ferreira, Cariste, Monteiro, Denapoli, Vrechi, Pereira, Gazzinelli, Lannes-Vieira, Rodrigues, Bortoluci and Vasconcelos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Moraschi BF, Noronha IH, Ferreira CP, Cariste LM, Monteiro CB, Denapoli P, Vrechi T, Pereira GJS, Gazzinelli RT, Lannes-Vieira J, Rodrigues MM, Bortoluci KR, Vasconcelos JRC. Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi. Front Cell Infect Microbiol. 2021 May 25;11:676183. doi: 10.3389/fcimb.2021.676183. PMID: 34123875; PMCID: PMC8191465. Link to article on publisher's site
Frontiers in cellular and infection microbiology
Moraschi BF, Noronha IH, Ferreira CP, Cariste LM, Monteiro CB, Denapoli P, Vrechi T, Pereira GJ, Gazzinelli RT, Lannes-Vieira J, Rodrigues MM, Bortoluci KR, Vasconcelos JR. (2021). Rapamycin Improves the Response of Effector and Memory CD8(+) T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi. Open Access Publications by UMMS Authors. https://doi.org/10.3389/fcimb.2021.676183. Retrieved from https://escholarship.umassmed.edu/oapubs/4729
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