T Cell Specificity: A Great Challenge in Chagas Disease

Ferragut, Fátima; Acevedo, Gonzalo Raúl; Gómez, Karina Andrea

doi:10.3389/fimmu.2021.674078

Cited by 17 publications

(12 citation statements)

References 90 publications

(124 reference statements)

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“…The immune response against T. cruzi substantially relies on T cells, and both CD4 + and CD8 + T lymphocytes are important to control parasite growth ( Tarleton et al., 1992 ; Tarleton et al., 1996 ; Martin and Tarleton, 2004 ; Dotiwala et al., 2016 ; Acevedo et al., 2018 ). Regarding the cytotoxic T lymphocyte (CTL) response, it is characterized by a strong immunodominance of epitopes derived from the Trans-sialidase (TS) family of proteins ( Tzelepis et al., 2008 ; Ferragut et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Biscari

Kaufman

Farré

et al. 2022

Front. Cell. Infect. Microbiol.

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Lipopolysaccharide (LPS) induces the activation of dendritic cells (DCs) throughout the engagement of toll-like receptor 4. LPS-activated DCs show increased capacity to process and present pathogen-derived antigens to activate naïve T cells. DCs-based vaccines have been successfully used to treat some cancer types, and lately transferred to the field of infectious diseases, in particular against HIV. However, there is no vaccine or DC therapy for any parasitic disease that is currently available. The immune response against Trypanosoma cruzi substantially relies on T cells, and both CD4+ and CD8+ T lymphocytes are required to control parasite growth. Here, we develop a vaccination strategy based on DCs derived from bone marrow, activated with LPS and loaded with TsKb20, an immunodominant epitope of the trans-sialidase family of proteins. We extensively characterized the CD8+ T cell response generated after immunization and compared three different readouts: a tetramer staining, ELISpot and Activation-Induced Marker (AIM) assays. To our knowledge, this work shows for the first time a proper set of T cell markers to evaluate specific CD8+ T cell responses in mice. We also show that our immunization scheme confers protection against T. cruzi, augmenting survival and reducing parasite burden in female but not male mice. We conclude that the immunization with LPS-activated DCs has the potential to prime significant CD8+ T cell responses in C57BL/6 mice independently of the sex, but this response will only be effective in female, possibly due to mice sexual dimorphisms in the response generated against T. cruzi.

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Section: Introductionmentioning

confidence: 99%

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Biscari

Kaufman

Farré

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Proteins are present in all living beings and participate in every cellular process, performing a range of functions in T. cruzi. Proteins are required for DNA replication, evasion, and the virulence mechanism, modulating the host invasion. Moreover, proteins present in mitochondria are essential for most biosynthetic pathways. , In the present work, the mass spectra of T.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de-N-Methylaplysinopsin

et al. 2022

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Chagas disease, caused by Trypanosoma cruzi , affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de- N -methylaplysinopsin ( BMA ) was isolated and chemically characterized from the marine coral Tubastraea tagusensis . BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi , resulting in IC 50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA , suggesting a different mechanism from benznidazole. In silico pharmacokinetic–pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations.

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“…The lack of identification of immunodominant fragments from parasite proteins recognized by T cells in patients with Chagas disease has also been influenced by other factors, such as protein abundance; proteasome peptide generation and transport; peptide affinity for the major histocompatibility complex (MHC); composition of the TCR repertoire, and competition between T cells for antigen-presenting cells, among others. However, a number of CD8 + T cell parasitic-derived epitopes have been described ( Ferragut et al., 2021 ).…”

Section: Search For Immunogenic Antigensmentioning

confidence: 99%

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research

Puerta

Cuéllar

Lasso

et al. 2023

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi, the causal agent of Chagas disease, has coexisted with humans for thousands of years. Therefore, the parasite has developed several mechanisms of antigenic variability that has allowed it to live inside the cells and evade the host immune response. Since T. cruzi displays an intracellular cycle-stage, our research team focused on providing insights into the CD8+ T cells immune response in chronic Chagas cardiomyopathy. We began our work in the 2000s studying parasite antigens that induce natural immune responses such as the KMP11 protein and TcTLE, its N-terminal derived peptide. Different approaches allowed us to reveal TcTLE peptide as a promiscuous CD8+ T cell epitope, able of inducing multifunctional cellular immune responses and eliciting a humoral response capable of decreasing parasite movement and infective capacity. Next, we demonstrated that as the disease progresses, total CD8+ T cells display a dysfunctional state characterized by a prolonged hyper-activation state along with an increase of inhibitory receptors (2B4, CD160, PD-1, TIM-3, CTLA-4) expression, an increase of specific terminal effector T cells (TTE), a decrease of proliferative capacity, a decrease of stem cell memory (TSCM) frequency, and a decrease of CD28 and CD3ζ expression. Thus, parasite-specific CD8+ T cells undergo clonal exhaustion, distinguished by an increase in late-differentiated cells, a mono-functional response, and enhanced expression of inhibitory receptors. Finally, it was found that anti-parasitic treatment induces an improved CD8+ T cell response in asymptomatic individuals, and a mouse animal model led us to establish a correlation between the quality of the CD8+ T cell responses and the outcome of chronic infection. In the future, using OMICs strategies, the identification of the specific cellular signals involved in disease progression will provide an invaluable resource for discovering new biomarkers of progression or new vaccine and immunotherapy strategies. Also, the inclusion of the TcTLE peptide in the rational design of epitope-based vaccines, the development of immunotherapy strategies using TSCM or the blocking of inhibitory receptors, and the use of the CD8+ T cell response quality to follow treatments, immunotherapies or vaccines, all are alternatives than could be explored in the fight against Chagas disease.

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T Cell Specificity: A Great Challenge in Chagas Disease

Cited by 17 publications

References 90 publications

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de-N-Methylaplysinopsin

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research

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