A novel multi-epitope recombinant protein elicits an antigen-specific CD8+ T cells response in Trypanosoma cruzi-infected mice

González-López, Cristina; Chen, Wen‐Hsiang; Alfaro-Chacón, Andrea; Villanueva‐Lizama, Liliana; Rosado-Vallado, Miguel; Ramírez-Sierra, María Jesús; Teh‐Poot, Christian; Pollet, Jeroen; Asojo, Oluwatoyin A.; Jones, Kathryn M.; Hotez, Peter J.; Bottazzi, María Elena; Cruz-Chan, Julio Vladimir

doi:10.1016/j.vaccine.2022.09.068

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…In this vein, our study reveals the presence of a highly conserved fragment of the Tc24 protein across TcI isolates from Mexico and from other countries in Latin America, thus providing a potential target for the development of a regional vaccine that could protect most of the people in risk areas where TcI is the main circulating genotype. Tc24 was postulated as a vaccine candidate, and was tested on murine [ 53 , 54 ], canine [ 55 ], and nonhuman primate [ 56 ] models, showing activity in decreasing the proliferation of parasites in the blood and decreasing cardiac damage in immunised animals.…”

Section: Discussionmentioning

confidence: 99%

The Low Variability of Tc24 in Trypanosoma cruzi TcI as an Advantage for Chagas Disease Prophylaxis and Diagnosis in Mexico

et al. 2023

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(1) Background: Chagas disease is the main neglected tropical disease in America. It is estimated that around 6 million people are currently infected with the parasite in Latin America, and 25 million live in endemic areas with active transmission. The disease causes an estimated economic loss of USD 24 billion dollars annually, with a loss of 75,200 working years per year of life; it is responsible for around ~12,000 deaths annually. Although Mexico is an endemic country that recorded 10,186 new cases of Chagas disease during the period of 1990–2017, few studies have evaluated the genetic diversity of genes that could be involved in the prophylaxis and/or diagnosis of the parasite. One of the possible candidates proposed as a vaccine target is the 24 kDa trypomastigote excretory–secretory protein, Tc24, whose protection is linked to the stimulation of T. cruzi-specific CD8+ immune responses. (2) Methods: The aim of the present study was to evaluate the fine-scale genetic diversity and structure of Tc24 in T. cruzi isolates from Mexico, and to compare them with other populations reported in the Americas with the aim to reconsider the potential role of Tc24 as a key candidate for the prophylaxis and improvement of the diagnosis of Chagas disease in Mexico. (3) Results: Of the 25 Mexican isolates analysed, 48% (12) were recovered from humans and 24% (6) recovered from Triatoma barberi and Triatoma dimidiata. Phylogenetic inferences revealed a polytomy in the T. cruzi clade with two defined subgroups, one formed by all sequences of the DTU I and the other formed by DTU II–VI; both subgroups had high branch support. Genetic population analysis detected a single (monomorphic) haplotype of TcI throughout the entire distribution across both Mexico and South America. This information was supported by Nei’s pairwise distances, where the sequences of TcI showed no genetic differences. (4) Conclusions: Given that both previous studies and the findings of the present work confirmed that TcI is the only genotype detected from human isolates obtained from various states of Mexico, and that there is no significant genetic variability in any of them, it is possible to propose the development of in silico strategies for the production of antigens that optimise the diagnosis of Chagas disease, such as quantitative ELISA methods that use this region of Tc24.

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Section: Discussionmentioning

confidence: 99%

The Low Variability of Tc24 in Trypanosoma cruzi TcI as an Advantage for Chagas Disease Prophylaxis and Diagnosis in Mexico

et al. 2023

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“…First-line drugs available to treat it have limited efficacy and are associated with toxicity. Therefore, there has been an increased interest in vaccine candidate development, exploring a variety of antigens, adjuvants and delivery systems (plasmids, adenoviruses, peptides and recombinant proteins) 27,31,[41][42][43][44][45] . The recombinant parasite-antigens TSA-1 and Tc24 have showed to reduce parasite burdens and increase antigen-specific T cells, as well as, survival of mice during experimental acute T. cruzi -infection 26,27,43,46 .…”

Section: Discussionmentioning

confidence: 99%

TSA-1-C4 plus Tc24-C4 recombinant protein stimulation induce immunomodulatory activity by activation of macrophages

Dzul-Huchim

Alfaro-Chacón

Novelo-Sarabia

et al. 2023

Preprint

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Chagas disease is a chronic infection caused by Trypanosoma cruzi. The first-line drugs approved for treatment have several limitations and are associated with toxicity. The recombinant TSA-1-C4 and Tc24-C4 proteins have been profiled as promising candidates for the formulation of therapeutic vaccines, leading us to propose them in combination as a bivalent recombinant protein strategy. In this study, we evaluated the immunomodulatory effect of TSA-1-C4 plus Tc24-C4 recombinant protein combination by in-vitro assays. Macrophages from naïve BALB/c mice were isolated and stimulated with TSA-1-C4+Tc24-C4 proteins, supernatants were recovered to measure NO, H O , and, TNF-α, IL-1β, IL-6 and IL-10 cytokines. Stimulated macrophages were co-cultured with CD8 T cells from naïve mice, and inflammatory cytokine-profile was measured from supernatants. Additionally, by experimental T. cruzi acute infection model, cytotoxicity was evaluated in mice after the treatment with TSA-1-C4+Tc24-C4 proteins in presence of a TLR-4 agonist adjuvant, E6020-SE. We observed that the bivalent recombinant protein strategy activates macrophages by NO and H O production, also induced a significant Th1 immune-response compared to either TSA-1-C4 or Tc24-C4 stimulated macrophages. Moreover, naïve CD8 T cells in presence of TSA-1-C4+Tc24-C4 stimulated-macrophages similarly boosted Th1 profile by significant production of IFN-γ and TNF-α cytokines. These results support the synergistic effect of the bivalent recombinant protein strategy, which leads activation of peritoneal macrophages and CD8 T cells eliciting the Th1 immune response. Although the administration of TSA-1-C4+Tc24-C4+E6020-SE showed cytotoxic activity in T. cruzi-infected mice, there was not a benefit compared to stimulate with TSA-1-C4 or Tc24-C4 antigens formulated with E6020-SE adjuvant.

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“…As Chagas disease remains a public health problem, so has the milestone of developing a vaccine to halt or delay the pathology by T. cruzi infection [14,[16][17][18]22]. Thus, an adequate murine model plays a key for the discovery and testing of new antigens in experimental…”

Section: Discussionmentioning

confidence: 99%

“…The chemotherapy of T. cruzi infections is based on nitrofurans and nitroimidazoles which are unsatisfactory since both compounds have toxic-side effects, ineffective in the chronic phase, and are associated with drug resistance [11,12]. An alternative approach is the development of a vaccine, which could be administered as immunotherapy either to individuals with acute or chronic infection to prevent the development of cardiomyopathy [13][14][15][16][17][18]. Nevertheless, despite efforts, a vaccine is still in preclinical studies and given the difficulties to perform non-human primates studies, there is an urgent need to optimize an adequate animal model that reproduces ECG and ECHO abnormalities which are the signature of Chagas disease cardiomyopathy [19].…”

Section: Introductionmentioning

confidence: 99%

Signature of cardiac alterations in early and late chronic infections with Trypanosoma cruzi in mice

Arias-Argáez,

Dzul-Huchim,

Haro-Álvarez

et al. 2023

PLoS ONE

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Chagas disease by Trypanosoma cruzi (T. cruzi) infection is a leading cause of myocarditis worldwide. Chagas cardiomyopathy is presented with a wide variety of conduction abnormalities including arrhythmias, first- and second-degree atrioventricular blockade, left ventricular systolic dysfunction and some cases heart failure leading to the death. Currently, there are no effective treatments available against advanced Chagas disease. With the advance in the development of novel therapies, it is important to utilize an animal model that can effectively replicate the diverse stages of Chagas disease, including chronic asymptomatic and symptomatic infection, that are akin to those observed in humans. Therefore, to characterize the cardiac alterations during the evolution of the infection, we evaluated the progression of cardiomyopathy caused by T. cruzi H1 infection in both BALB/c and ICR mouse models by performing electrocardiogram (ECG) studies in unanesthetized mice every month until 210 days post-infection (dpi). In the late chronic phase of infection, we also performed echocardiogram (ECHO) studies to further assess cardiac function. In conclusion, we demonstrated that ICR mice were more susceptible to cardiac alterations compared to BALB/c mice and both mouse strains are suitable experimental models to study chronic T. cruzi infection and novel treatments.

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A novel multi-epitope recombinant protein elicits an antigen-specific CD8+ T cells response in Trypanosoma cruzi-infected mice

Cited by 8 publications

References 20 publications

The Low Variability of Tc24 in Trypanosoma cruzi TcI as an Advantage for Chagas Disease Prophylaxis and Diagnosis in Mexico

The Low Variability of Tc24 in Trypanosoma cruzi TcI as an Advantage for Chagas Disease Prophylaxis and Diagnosis in Mexico

TSA-1-C4 plus Tc24-C4 recombinant protein stimulation induce immunomodulatory activity by activation of macrophages

Signature of cardiac alterations in early and late chronic infections with Trypanosoma cruzi in mice

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