Genetic Vaccination against Experimental Infection with Myotropic Parasite Strains of<i>Trypanosoma cruzi</i>

Araújo, Adriano Fernando; Oliveira, Gabriel de; Vasconcelos, Juliana Fraga; Ersching, Jonatan; Dominguez, Mariana Ribeiro; Vasconcelos, José Ronnie; Machado, Alexandre Vieira; Gazzinelli, Ricardo T.; Bruna-Romero, Oscar; Soares, Milena Botelho Pereira; Rodrigues, Maurício M.

doi:10.1155/2014/605023

Cited by 10 publications

(12 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although TCM cells have been reported to provide superior long-term protection against systemic infections ( Zaph et al., 2004 ; Klebanoff et al., 2005 ; Angelosanto and Wherry, 2010 ), this memory phenotype does not necessarily represent higher quality ( Lanzavecchia and Sallusto, 2005 ). Indeed, CD8 + TEM cells generated by heterologous prime-boost immunization protocol confer immunity and protection against T. cruzi in acute and chronic infections ( De Alencar et al., 2009 ; Haolla et al., 2009 ; Rigato et al., 2011 ; Araújo et al., 2014 ). TEM CD8 + T cells can respond fast during recall and this quality is crucial for protection of individuals in endemic areas.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Moraschi

Noronha

Ferreira

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

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 (IFNγ) 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Moraschi

Noronha

Ferreira

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…Those authors reported that as alterations in the humoral T. cruzi-specific response were ruled out, hormones like estradiol could play a relevant role on the higher vulnerability of male than female mice (19). Also, because T. cruzi infection in mammalian hosts leads to diverse clinical manifestations, and because this may be partly due to the occurrence of different parasite strains, experiments evaluating vaccination or chemotherapy should take into consideration the use of distinct DTUs relevant for human infection (20).…”

Section: Discussionmentioning

confidence: 99%

Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

Guedes-da-Silva

Batista

Silva

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD. (1), is a neglected pathology caused by the obligately intracellular protozoan parasite Trypanosoma cruzi. The disease is endemic in 21 countries of Central and South America, where about 8 million people are infected and more than 12,000 die annually (http: //www.dndial.org). The treatment for CD is limited to the use of two nitroderivatives (benznidazole [Bz] and nifurtimox [Nf]), which are largely unsatisfactory, indicating a need for novel, safer, and more efficient therapies (2). Although a large number of in vitro and in vivo studies have been performed on experimental chemotherapy of novel drug candidates for CD, besides Bz and Nf, very few compounds have moved to clinical trials (3). C hagas disease (CD), discovered by Carlos ChagasRecently, two antifungal drugs, posaconazole and E1224 (the prodrug of ravuconazole), which are inhibitors of fungal sterol 14a-demethylase (CYP51), were evaluated as potential antichagasic drugs on chronic patients, but unfortunately both displayed rather high (70 to 80%) rates of therapeutic failure (4, 5). It has been suggested that at least part of this unexpected failure could be due to the lack of translation from in vitro and in vivo models to the clinic and that a redesign of the current screening strategy during the drug discovery process should be considered (5). On the other hand, recent data demonstrated the potency and selectivity of a novel experimental inhibitor of T. cruzi CYP51, the VNI molecule, which yielded promising in vivo findings even with highly resistant T. cruzi strains (6). In this vein, we evaluated the effects and outco...

show abstract

“…Chagas disease [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. These antigens are an amastigote surface protein, the ASP-2, and the virulence factor named TS, which is primarily expressed by the trypomastigotes [54,55].…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, we used the members of the transialidase family amastigote surface protein-2 (ASP-2) and Transialidase (TS) as vaccine candidates. We have used the adjuvanted proteins, plasmids, influenza PR8 vector, as well as the human Adenovirus 5 (hAd5) encoding either ASP-2 or TS proteins (hAd-ASP2 and hAd-TS, respectively) [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. The most effective protocol used in our lab employs a priming with a combination of plasmids encoding ASP-2 and TS followed by a boost with the hAd-ASP2 and hAd-TS, 21 days apart.…”

Section: Introductionmentioning

confidence: 99%

Immunization with a recombinant ASP-2/Transialidase chimeric protein induces robust protective immunity in both murine and canine models of Chagas’ disease

Gazzinelli

Castro

Brito

et al. 2022

Preprint

View full text Add to dashboard Cite

We have systematically shown that the Amastigote Surface Protein-2 (ASP-2) and Transialidase (TS) antigens either in the form of recombinant protein or encoded in the plasmids and human adenovirus 5 (hAd5) confer strong protection against different lineages of Trypanosoma cruzi parasites. Herein we generated a chimeric protein containing the most immunogenic regions for T and B cells from ASP-2 and TS (DTT-1) and evaluated its efficacy in comparison with our standard protocol of heterologous prime-boost using plasmids and hAd5. Our results show that mice immunized with DTT-1 protein together with Poly-ICLC (Hiltonol) become highly resistant to challenge with the Y strain of T. cruzi, showing a large decrease in tissue parasitism, parasitemia and no lethality. This protection lasted for at least 3 months after the last boost of immunization and an equivalent level of protection induced by the DNA/hAd5 protocol. DTT-1 induced high levels of T. cruzi-specific antibodies and IFNγ-producing T cells and protection was mediated by B lymphocytes, CD8 T cells and IFNγ. Finally, we evaluated the toxicity, immunogenicity and efficacy of the DTT-1 and DNA/hAd5 formulations in dogs. Mild collateral effects were detected at the site of vaccine inoculation. While the chimeric protein associated to Poly-ICLC induced high levels of antibodies and CD4+ T cell responses, the DNA/hAd5 induced no antibodies, but a strong CD8+ T cell response. Immunization with either vaccine formulations protected dogs against challenge with the Berenice strain of T. cruzi. Despite to the similar efficacy, we conclude that moving ahead with DTT-1 together with Hiltonol is advantageous over the hAd5 vaccine due to the cost-benefit for development and large-scale production.

show abstract

Genetic Vaccination against Experimental Infection with Myotropic Parasite Strains ofTrypanosoma cruzi

Cited by 10 publications

References 36 publications

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

Immunization with a recombinant ASP-2/Transialidase chimeric protein induces robust protective immunity in both murine and canine models of Chagas’ disease

Contact Info

Product

Resources

About