State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response

Cortes-Serra, Núria; Losada, Irene; Pinazo, María Jesús; Fernández-Becerra, Carmen; Gascón, Joaquim; Alonso-Padilla, Julio

doi:10.1016/j.bbadis.2020.165758

Cited by 25 publications

(20 citation statements)

References 79 publications

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“…gov, NCT02369978) is a placebocontrolled trial that will evaluate half standard doses of NFX and BZN for 120 days (240 mg/day for NFX and 150 mg/day for BZN) in comparison with the SoC of both drugs (480 mg/day/60 days for NFX and 300 mg/day/60 days for BZN). The efficacy will be evaluated by PCR at 12-18 months of follow-up and by changes in the levels of B-type natriuretic peptides, a suggested surrogated BMK for CD cure, 27 and also by CS. 112 The MULTIBENZ ("Evaluation of Different Benznidazole Regimens for the Treatment of Chronic Chagas Disease") study ( ClinicalTrials.…”

Section: Discussionmentioning

confidence: 99%

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

et al. 2021

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IntroductionChagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs.Methods and analysisNew ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping.Ethics and disseminationThe TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions.Trial registration numberNCT03981523.

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Section: Discussionmentioning

confidence: 99%

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

et al. 2021

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“…As reviewed by Cortes‐Serra et al ., 11 many biomarkers, including autoantibodies, have been associated with ChD cardiomyopathy, whose levels increase with symptomatology, but most of them are unable to distinguish between ChD cardiomyopathy and other cardiomyopathies. Contrarily, autoantibodies against sCha are Chagas cardiomyopathy–specific, not described for any other cardiomyopathy, and not present in healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers of cardiac damage and inflammation commonly used for the prognosis of other cardiomyopathies that have been tested in chagasic patients (ChP), but there is no single molecule that meets all the required expectations to implement in endemic countries (reviewed in Ref. 11). There are also promising studies evaluating the efficacy of treatment by PCR, and enzyme‐linked immunosorbent assay (ELISA) but still better biomarkers are needed (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, many autoantigens are recognized by antibodies present in the serum of ChP 11 as a result of molecular mimicry (similarity of amino acid sequences between parasite and host antigens) 10,13,14 . The β1‐adrenergic 15 and muscarinic M2 16 receptors, and cardiac myosin 17,18 are the targets of autoantibodies in ChD and likely related to cardiac pathology.…”

Section: Introductionmentioning

confidence: 99%

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Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy

Rodríguez-Angulo

Lamsfus‐Calle

Isoler-Alcaráz

et al. 2021

Annals of the New York Academy of Sciences

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In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix‐loop‐helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti‐sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross‐reactivity with sCha, confirming the role of molecular mimicry in the development of anti‐sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death.

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“…Several studies in Chagasic patients or animal models with chronic T. cruzi infection have suggested a relationship between T cell responses and ChD severity ( Pinazo et al., 2015 ; Cortes-Serra et al., 2020 ). However, validating this hypothesis has been difficult because of the natural ChD history, which makes the long-term follow-up of patients for decades after the initial infection complex.…”

Section: Introductionmentioning

confidence: 99%

CD8+ T Cell Response Quality Is Related to Parasite Control in an Animal Model of Single and Mixed Chronic Trypanosoma cruzi Infections

Mateus

Nocua

Lasso

et al. 2021

Front. Cell. Infect. Microbiol.

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Chagas disease (ChD) is a chronic infection caused by Trypanosoma cruzi. This highly diverse intracellular parasite is classified into seven genotypes or discrete typing units (DTUs) and they overlap in geographic ranges, vectors, and clinical characteristics. Although studies have suggested that ChD progression is due to a decline in the immune response quality, a direct relationship between T cell responses and disease outcome is still unclear. To investigate the relationship between parasite control and immune T cell responses, we used two distinct infection approaches in an animal model to explore the histological and parasitological outcomes and dissect the T cell responses in T. cruzi-infected mice. First, we performed single infection experiments with DA (TcI) or Y (TcII) T. cruzi strains to compare the infection outcomes and evaluate its relationship with the T cell response. Second, because infections with diverse T. cruzi genotypes can occur in naturally infected individuals, mice were infected with the Y or DA strain and subsequently reinfected with the Y strain. We found different infection outcomes in the two infection approaches used. The single chronic infection showed differences in the inflammatory infiltrate level, while mixed chronic infection by different T. cruzi DTUs showed dissimilarities in the parasite loads. Chronically infected mice with a low inflammatory infiltrate (DA-infected mice) or low parasitemia and parasitism (Y/Y-infected mice) showed increases in early-differentiated CD8+ T cells, a multifunctional T cell response and lower expression of inhibitory receptors on CD8+ T cells. In contrast, infected mice with a high inflammatory infiltrate (Y-infected mice) or high parasitemia and parasitism (DA/Y-infected mice) showed a CD8+ T cell response distinguished by an increase in late-differentiated cells, a monofunctional response, and enhanced expression of inhibitory receptors. Overall, our results demonstrated that the infection outcomes caused by single or mixed T. cruzi infection with different genotypes induce a differential immune CD8+ T cell response quality. These findings suggest that the CD8+ T cell response might dictate differences in the infection outcomes at the chronic T. cruzi stage. This study shows that the T cell response quality is related to parasite control during chronic T. cruzi infection.

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State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response

Cited by 25 publications

References 79 publications

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy

CD8+ T Cell Response Quality Is Related to Parasite Control in an Animal Model of Single and Mixed Chronic Trypanosoma cruzi Infections

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