Probing for Trypanosoma cruzi Cell Surface Glycobiomarkers for the Diagnosis and Follow-Up of Chemotherapy of Chagas Disease

2017 ◽  
pp. 195-211
Author(s):  
Nathaniel S. Schocker ◽  
Susana Portillo ◽  
Roger A. Ashmus ◽  
Carlos R. N. Brito ◽  
Igor E. Silva ◽  
...  
Keyword(s):  
Cell Surface ◽  
Trypanosoma Cruzi ◽  
Chagas Disease

scholarly journals Trypanosoma cruzi Phosphomannomutase and Guanosine Diphosphate-Mannose Pyrophosphorylase Ligandability Assessment

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Filip Zmuda ◽  
Sharon M. Shepherd ◽  
Michael A. J. Ferguson ◽  
David W. Gray ◽  
Leah S. Torrie ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Surface ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
De Novo ◽  
Chemical Space ◽  
Nucleotide Sugar ◽  
Content Type ◽  
Life Cycle Stages ◽  
Drug Discovery Program

ABSTRACT Chagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. Therefore, there is a clinical need for new therapeutic agents that can mitigate these issues. The phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GDP-MP) enzymes form part of the de novo biosynthetic pathway to the nucleotide sugar GDP-mannose. This nucleotide sugar is used either directly, or indirectly via the formation of dolichol-phosphomannose, for the assembly of all mannose-containing glycoconjugates. In T. cruzi, mannose-containing glycoconjugates include the cell-surface glycoinositol-phospholipids and the glycosylphosphatidylinositol-anchored mucin-like glycoproteins that dominate the cell surface architectures of all life cycle stages. This makes PMM and GDP-MP potentially attractive targets for a drug discovery program against Chagas’ disease. To assess the ligandability of these enzymes in T. cruzi, we have screened 18,117 structurally diverse compounds exploring drug-like chemical space and 16,845 small polar fragment compounds using an assay interrogating the activities of both PMM and GDP-MP enzymes simultaneously. This resulted in 48 small fragment hits, and on retesting 20 were found to be active against the enzymes. Deconvolution revealed that these were all inhibitors of T. cruzi GDP-MP, with compounds 2 and 3 acting as uncompetitive and competitive inhibitors, respectively. Based on these findings, the T. cruzi PMM and GDP-MP enzymes were deemed not ligandable and poorly ligandable, respectively, using small molecules from conventional drug discovery chemical space. This presents a significant hurdle to exploiting these enzymes as therapeutic targets for Chagas’ disease.

scholarly journals Long term follow-up of Trypanosoma cruzi infection and Chagas disease manifestations in mice treated with benznidazole or posaconazole

2020 ◽  
Vol 14 (9) ◽  
pp. e0008726
Author(s):  
Claudia Magalhães Calvet ◽  
Tatiana Araújo Silva ◽  
Diane Thomas ◽  
Brian Suzuki ◽  
Ken Hirata ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Long Term Follow Up ◽  
Cruzi Infection

scholarly journals The Trypomastigote Small Surface Antigen from Trypanosoma cruzi Improves Treatment Evaluation and Diagnosis in Pediatric Chagas Disease

2017 ◽  
Vol 55 (12) ◽  
pp. 3444-3453 ◽  
Author(s):  
Virginia Balouz ◽  
Luciano J. Melli ◽  
Romina Volcovich ◽  
Guillermo Moscatelli ◽  
Samanta Moroni ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Surface Antigen ◽  
Rapid Assessment ◽  
Drug Efficacy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serological Tests ◽  
Small Surface ◽  
Content Type

ABSTRACTChagas disease is caused by the protozoan parasiteTrypanosoma cruzi. Assessment of parasitological cure upon treatment with available drugs relies on achieving consistent negative results in conventional parasitological and serological tests, which may take years to assess. Here, we evaluated the use of a recombinantT. cruziantigen termed trypomastigote small surface antigen (TSSA) as an early serological marker of drug efficacy inT. cruzi-infected children. A cohort of 78 pediatric patients born toT. cruzi-infected mothers was included in this study. Only 39 of the children were infected withT. cruzi, and they were immediately treated with trypanocidal drugs. Serological responses against TSSA were evaluated in infected and noninfected populations during the follow-up period using an in-house enzyme-linked immunosorbent assay (ELISA) and compared to conventional serological methods. Anti-TSSA antibody titers decreased significantly faster than anti-whole parasite antibodies detected by conventional serology both inT. cruzi-infected patients undergoing effective treatment and in those not infected. The differential kinetics allowed a significant reduction in the required follow-up periods to evaluate therapeutic responses or to rule out maternal-fetal transmission. Finally, we present the case of a congenitally infected patient with an atypical course in whom TSSA provided an early marker forT. cruziinfection. In conclusion, we showed that TSSA was efficacious both for rapid assessment of treatment efficiency and for early negative diagnosis in infants at risk of congenitalT. cruziinfection. Based upon these findings we propose the inclusion of TSSA for refining the posttherapeutic cure criterion and other diagnostic needs in pediatric Chagas disease.

Incidence and Predictors of Progression to Chagas Cardiomyopathy: Long-Term Follow-Up of Trypanosoma Cruzi Seropositive Individuals

Circulation ◽  
2021 ◽  
Author(s):  
Maria Carmo P. Nunes ◽  
Lewis F. Buss ◽  
Jose Luiz P. da Silva ◽  
Larissa Natany Almeida Martins ◽  
Claudia Di Lorenzo Oliveira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Clinical Epidemiology ◽  
Outpatient Service ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Blood Collection ◽  
Ventricular Ejection Fraction ◽  
Chagas Cardiomyopathy

Background: There are few contemporary cohorts of Trypanosoma cruzi -seropositive individuals, and the basic clinical epidemiology of Chagas disease is poorly understood. Herein, we report the incidence of cardiomyopathy and death associated with T. cruzi seropositivity. Methods: Participants were selected in blood banks at 2 Brazilian centers. Cases were defined as T. cruzi -seropositive blood donors. T. cruzi -seronegative controls were matched for age, sex, and period of donation. Patients with established Chagas cardiomyopathy were recruited from a tertiary outpatient service. Participants underwent medical examination, blood collection, electrocardiogram, and echocardiogram at enrollment (2008 to 2010) and at follow-up (2018 to 2019). The primary outcomes were all-cause mortality and development of cardiomyopathy, defined as the presence of a left ventricular ejection fraction <50% and/or QRS complex duration ≥ 120 ms. To handle loss to follow-up, a sensitivity analysis was performed using inverse probability weights for selection. Results: We enrolled 499 T. cruzi -seropositive donors (age 48 ± 10 years, 52% male), 488 T. cruzi -seronegative donors (age 49 ± 10 years, 49% male), and 101 patients with established Chagas cardiomyopathy (age 48 ± 8 years, 59% male). The mortality in patients with established cardiomyopathy was 80.9 deaths/1000 person-years (py) (54/101, 53%) and 15.1 deaths/1000py (17/114, 15%) in T. cruzi -seropositives with cardiomyopathy at baseline. Among T. cruzi -seropositive donors without cardiomyopathy at baseline mortality was 3.7 events/1000py (15/385, 4%), which was no different from T. cruzi -seronegative donors with 3.6 deaths/1000py (17/488, 3%). The incidence of cardiomyopathy in T. cruzi -seropositive donors was 13.8 (95% CI 9.5-19.6) events/1000py (32/262, 12%) compared with 4.6 (95% CI 2.3-8.3) events/1000 py (11/277, 4%) in seronegative controls, with an absolute incidence difference associated with T. cruzi seropositivity of 9.2 (95% CI 3.6 - 15.0) events/1000py. T. cruzi antibody level at baseline was associated with development of cardiomyopathy (adjusted OR of 1.4, 95% CI 1.1-1.8). Conclusions: We present a comprehensive description of the natural history of T. cruzi seropositivity in a contemporary patient population. The results highlight the central importance of anti- T. cruzi antibody titer as a marker of Chagas disease activity and risk of progression.

scholarly journals A Brief View of the Surface Membrane Proteins fromTrypanosoma cruzi

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Ángel de la Cruz Pech-Canul ◽  
Victor Monteón ◽  
Rosa-Lidia Solís-Oviedo
Keyword(s):  
Life Cycle ◽  
Membrane Proteins ◽  
South America ◽  
Cell Surface ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Surface Membrane ◽  
Surface Molecules ◽  
The World ◽  
Large Families

Trypanosoma cruziis the causal agent of Chagas’ disease which affects millions of people around the world mostly in Central and South America.T. cruziexpresses a wide variety of proteins on its surface membrane which has an important role in the biology of these parasites. Surface molecules of the parasites are the result of the environment to which the parasites are exposed during their life cycle. Hence,T. cruzidisplays several modifications when they move from one host to another. Due to the complexity of this parasite’s cell surface, this review presents some membrane proteins organized as large families, as they are the most abundant and/or relevant throughout theT. cruzimembrane.

scholarly journals Hyperglycemia associated with Chagas disease

2022 ◽  
Vol 3 (6) ◽  
pp. 1-5
Author(s):  
Imelda Menchaca Armenta ◽  
Antonio E. Gutiérrez Rodríguez ◽  
Hortencia Cortes Pérez ◽  
Jessica Zaragoza Cortes ◽  
Karen Zamora Cerritos
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Screening Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chi Square ◽  
Long Term Follow Up ◽  
Chi Square Test ◽  
Years Lived With Disability

Chagas disease and type 2 diabetes mellitus are the two main causes of Years Lived with Disability. The consequences and possible interaction between both illnesses have been scarcely studied. A population study of blood donors from the Centro Estatal de Transfusión Sanguinea (CETS) was carried out with a reagent related to the Chagas test. Detection was carried out with an enzyme-linked immunosorbent assay (ELISA) of anti- Trypanosoma cruzi antibodies and also, an HbA1C test was performed with 4 mL of whole blood. Descriptive statistics were used to analyze quantitative and qualitative data. The Chi-square test was applied to determine the existence of an association between hyperglycemia and Chagas disease. A total of 4,952 participants were screened. All of the participants (100%) were from Hidalgo State and did not have a chagoma as evidence of having been bitten or denied contact with a “kissing bug”. Of the total, 26 reacted to the first screening test to detect anti-Trypanosoma cruzi antibodies; of these, five were confirmed as positive on the second screening test. The seroprevalence of T. cruzi was 0.01%. The results do not show a clear association but the frequency of hyperglycemia in population with Chagas coincides with that reported by other authors. Considering the scarce clinical–epidemiological evidence between Chagas disease, obesity, and hyperglycemia, long-term follow up of both morbidities is an area of opportunity for clinical and epidemiological study of T. cruzi reactivity.

scholarly journals Trypanosoma cruzi infection follow-up in a sylvatic vector of Chagas disease: Comparing early and late stage nymphs

2021 ◽  
Vol 15 (9) ◽  
pp. e0009729
Author(s):  
Valeria Cortés ◽  
Amalia Cruz ◽  
Sofia Onetti ◽  
Daniela Kinzel ◽  
Javiera Garcia ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Late Stage ◽  
Rectal Wall ◽  
Underlying Mechanism ◽  
First Feeding ◽  
Infection Dynamics ◽  
Two Samples ◽  
Cruzi Infection

Chagas disease is caused by Trypanosoma cruzi and transmitted by the triatomine Mepraia spinolai in the southwest of South America. Here, we examined the T. cruzi-infection dynamics of field-caught M. spinolai after laboratory feeding, with a follow-up procedure on bug populations collected in winter and spring of 2017 and 2018. Bugs were analyzed twice to evaluate T. cruzi-infection by PCR assays of urine/fecal samples, the first evaluation right after collection and the second 40 days after the first feeding. We detected bugs with: the first sample positive and second negative (+/-), the first sample negative and second positive (-/+), and with both samples positive or negative (+/+; -/-). Bugs that resulted positive on both occasions were the most frequent, with the exception of those collected in winter 2018. Infection rate in spring was higher than winter only in 2018. Early and late stage nymphs presented similar T. cruzi-infection rates except for winter 2017; therefore, all nymphs may contribute to T. cruzi-transmission to humans. Assessment of infection using two samples represents a realistic way to determine the infection a triatomine can harbor. The underlying mechanism may be that some bugs do not excrete parasites unless they are fed and maintained for some time under environmentally controlled conditions before releasing T. cruzi, which persists in the vector hindgut. We suggest that T. cruzi-infection dynamics regarding the three types of positive-PCR results detected by follow-up represent: residual T. cruzi in the rectal lumen (+/-), colonization of parasites attached to the rectal wall (-/+), and presence of both kinds of flagellates in the hindgut of triatomines (+/+). We suggest residual T. cruzi-infections are released after feeding, and result 60–90 days after infection persisting in the rectal lumen after a fasting event, a phenomenon that might vary between contrasting seasons and years.

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