Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 20.164
Filter
1.
PLoS One ; 19(6): e0304716, 2024.
Article in English | MEDLINE | ID: mdl-38829872

ABSTRACT

Optical microscopy videos enable experts to analyze the motion of several biological elements. Particularly in blood samples infected with Trypanosoma cruzi (T. cruzi), microscopy videos reveal a dynamic scenario where the parasites' motions are conspicuous. While parasites have self-motion, cells are inert and may assume some displacement under dynamic events, such as fluids and microscope focus adjustments. This paper analyzes the trajectory of T. cruzi and blood cells to discriminate between these elements by identifying the following motion patterns: collateral, fluctuating, and pan-tilt-zoom (PTZ). We consider two approaches: i) classification experiments for discrimination between parasites and cells; and ii) clustering experiments to identify the cell motion. We propose the trajectory step dispersion (TSD) descriptor based on standard deviation to characterize these elements, outperforming state-of-the-art descriptors. Our results confirm motion is valuable in discriminating T. cruzi of the cells. Since the parasites perform the collateral motion, their trajectory steps tend to randomness. The cells may assume fluctuating motion following a homogeneous and directional path or PTZ motion with trajectory steps in a restricted area. Thus, our findings may contribute to developing new computational tools focused on trajectory analysis, which can advance the study and medical diagnosis of Chagas disease.


Subject(s)
Microscopy, Video , Trypanosoma cruzi , Trypanosoma cruzi/physiology , Microscopy, Video/methods , Chagas Disease/parasitology , Humans , Image Processing, Computer-Assisted/methods
2.
J Biomed Sci ; 31(1): 58, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824576

ABSTRACT

BACKGROUND: A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques. METHODS: We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires. RESULTS: RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose. CONCLUSIONS: These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.


Subject(s)
Chagas Disease , Macaca mulatta , Protozoan Vaccines , Receptors, Antigen, T-Cell , Animals , Chagas Disease/immunology , Chagas Disease/prevention & control , Receptors, Antigen, T-Cell/immunology , Protozoan Vaccines/immunology , Trypanosoma cruzi/immunology , Immunoglobulins/immunology
3.
Sci Rep ; 14(1): 10039, 2024 05 02.
Article in English | MEDLINE | ID: mdl-38693166

ABSTRACT

According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.


Subject(s)
Chagas Disease , Molecular Docking Simulation , Molecular Dynamics Simulation , Trypanosoma cruzi , Trypanosoma cruzi/enzymology , Trypanosoma cruzi/drug effects , Chagas Disease/drug therapy , Chagas Disease/parasitology , Humans , Proto-Oncogene Proteins c-akt/metabolism , Protozoan Proteins/metabolism , Protozoan Proteins/chemistry , Protozoan Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Binding
4.
Parasit Vectors ; 17(1): 208, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38720313

ABSTRACT

BACKGROUND: Triatoma infestans, Triatoma brasiliensis, Triatoma pseudomaculata and Rhodnius prolixus are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Chickens serve as an important blood food source for triatomines. This study aimed to assess the insecticidal activity of fluralaner (Exzolt®) administered to chickens against triatomines (R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata). METHODS: Twelve non-breed chickens (Gallus gallus domesticus) were randomized based on weight into three groups: negative control (n = 4); a single dose of 0.5 mg/kg fluralaner (Exzolt®) (n = 4); two doses of 0.5 mg/kg fluralaner (Exzolt®) (n = 4). Nymphs of 3rd, 4th and 5th instars of R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata (all n = 10) were allowed to feed on chickens before treatment, and at intervals of 1, 7, 14, 21, 28, 35 and 56 days after treatment, with insect mortality determined. RESULTS: Treatment with two doses of fluralaner showed higher insecticidal efficacy against R. prolixus, T. infestans and T. brasiliensis compared to the single-dose treatment. Similar insecticidal efficacy was observed for T. pseudomaculata for one and two doses of fluralaner. Insecticidal activity of fluralaner (Exzolt®) against triatomine bugs was noted up to 21 and 28 days after treatment with one and two doses of fluralaner, respectively. CONCLUSIONS: The results demonstrate that treatment of chickens with fluralaner (Exzolt®) induces insecticidal activity against triatomines for up to 28 days post-treatment, suggesting its potential use as a control strategy for Chagas disease in endemic areas.


Subject(s)
Chickens , Insecticides , Isoxazoles , Animals , Chickens/parasitology , Isoxazoles/pharmacology , Isoxazoles/administration & dosage , Insecticides/pharmacology , Insecticides/administration & dosage , Insect Vectors/drug effects , Chagas Disease/transmission , Chagas Disease/drug therapy , Chagas Disease/veterinary , Triatominae , Nymph/drug effects , Poultry Diseases/parasitology , Poultry Diseases/prevention & control , Triatoma/drug effects
5.
Tidsskr Nor Laegeforen ; 144(6)2024 May 14.
Article in English, Norwegian | MEDLINE | ID: mdl-38747663

ABSTRACT

Background: Chagas encephalitis is a rare but severe manifestation of reactivation in patients with chronic Chagas disease. Case presentation: A woman in her seventies who was immunosuppressed after a heart transplant due to Chagas disease was admitted with convulsions, headache and visual disturbances. She developed fever, confusion and repeated convulsions. Pleocytosis was found in spinal fluid. Wet-mount microscopy of spinal fluid revealed motile Trypanosoma cruzi trypomastigotes, and multiple trypomastigotes were seen on a Giemsa-stained smear, confirming reactivation of Chagas disease with meningoencephalitis. Despite benznidazole treatment, she deteriorated, exhibiting pharyngeal paralysis, aphasia and increasing somnolence. Brain CT showed pathology consistent with Chagas encephalitis. Nifurtimox was given as an adjunctive treatment. After a week of treatment, the patient began to improve. She completed 60 days of benznidazole and had regained normal cognitive and neurological function on subsequent follow-up. She had no signs of myocarditis reactivation. Interpretation: Chronic Chagas disease is common among Latin American immigrants in Europe. Reactivation with myocarditis after a heart transplant is well known, while encephalitis is a rare manifestation. We report on a case of Chagas encephalitis in an immunosuppressed patient. Microscopy of parasites in spinal fluid revealed the diagnosis. The WHO provided antiparasitic medications, and despite a severe prognosis, the patient made a full recovery.


Subject(s)
Seizures , Humans , Female , Seizures/etiology , Seizures/drug therapy , Aged , Fever/etiology , Chagas Disease/drug therapy , Trypanocidal Agents/therapeutic use , Immunocompromised Host
6.
Vet Parasitol Reg Stud Reports ; 51: 101031, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38772647

ABSTRACT

The Mexican free-tailed bat (Tadarida brasiliensis) is one of the most abundant mammals in North America. Mexican free-tailed bats have a wide geographic range stretching from northern South America to the western United States. Bats are theorized to be the original hosts for Trypanosoma cruzi -the causative agent of Chagas disease- and can serve as a source of infection to triatomine insect vectors that feed upon them. Chagas disease is a neglected tropical disease across the Americas where triatomines are present, including the southern United States, where Texas reports this highest number of locally-acquired human cases. To learn more about the role of bats in the ecology of Chagas disease in Texas, we surveyed a colony of Mexican free-tailed bats from Brazos County, Texas, for T. cruzi using carcasses salvaged after an extreme weather event. A total of 283 Mexican free-tailed bats collected in February 2021 were dissected and DNA from the hearts and kidneys was used for T. cruzi detection via qPCR. None of the bat hearts or kidneys tested positive for T. cruzi; this sample size affords 95% confidence that the true prevalence of T. cruzi in this population does not exceed 1%. Future sampling of multiple bat species as well as migrant and resident colonies of Mexican free-tailed bats across different times of the year over a broader geographic range would be useful in learning more about the role of bats in the ecology of Chagas disease in Texas.


Subject(s)
Chagas Disease , Chiroptera , Trypanosoma cruzi , Animals , Chiroptera/parasitology , Texas/epidemiology , Trypanosoma cruzi/isolation & purification , Chagas Disease/veterinary , Chagas Disease/epidemiology , Chagas Disease/parasitology , Male , Female
7.
Nat Commun ; 15(1): 4400, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38782898

ABSTRACT

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.


Subject(s)
Chagas Disease , Disease Models, Animal , Enteric Nervous System , Mice, Inbred C3H , Nitroimidazoles , Trypanocidal Agents , Trypanosoma cruzi , Animals , Chagas Disease/drug therapy , Chagas Disease/parasitology , Female , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Nitroimidazoles/pharmacology , Nitroimidazoles/therapeutic use , Trypanosoma cruzi/drug effects , Mice , Enteric Nervous System/drug effects , Nerve Regeneration/drug effects
8.
Expert Opin Drug Discov ; 19(6): 741-753, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38715393

ABSTRACT

INTRODUCTION: Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD. AREAS COVERED: Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi, aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD. EXPERT OPINION: Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.


Subject(s)
Chagas Disease , Drug Discovery , Drug Resistance , Nitroimidazoles , Trypanocidal Agents , Trypanosoma cruzi , Trypanosoma cruzi/drug effects , Nitroimidazoles/pharmacology , Chagas Disease/drug therapy , Chagas Disease/parasitology , Trypanocidal Agents/pharmacology , Humans , Animals , Drug Discovery/methods , Drug Development
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124346, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38692105

ABSTRACT

Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.


Subject(s)
Chagas Disease , Molecular Conformation , Nifurtimox , Chagas Disease/drug therapy , Nifurtimox/chemistry , Spectrophotometry, Ultraviolet , Trypanocidal Agents/chemistry , Models, Molecular , Density Functional Theory , Trypanosoma cruzi/drug effects , Solvents/chemistry
10.
Biomed Pharmacother ; 175: 116742, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38754265

ABSTRACT

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.


Subject(s)
Amiodarone , Chagas Cardiomyopathy , Disease Models, Animal , Drug Therapy, Combination , Mice, Inbred C57BL , Nitroimidazoles , Trypanocidal Agents , Trypanosoma cruzi , Animals , Nitroimidazoles/pharmacology , Nitroimidazoles/administration & dosage , Nitroimidazoles/therapeutic use , Female , Trypanosoma cruzi/drug effects , Amiodarone/pharmacology , Amiodarone/administration & dosage , Chagas Cardiomyopathy/drug therapy , Chagas Cardiomyopathy/parasitology , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Mice , Chagas Disease/drug therapy , Chagas Disease/parasitology , Reactive Oxygen Species/metabolism , Chronic Disease , Parasitemia/drug therapy , Parasitemia/parasitology , Tumor Necrosis Factor-alpha/metabolism , Parasite Load
11.
Int J Mol Sci ; 25(10)2024 May 18.
Article in English | MEDLINE | ID: mdl-38791565

ABSTRACT

Currently, approximately 70% of new cases of Chagas disease (CD) in Brazil are attributed to oral transmission, particularly through foods such as açaí, bacaba, and sugarcane juice, primarily in the northern and northeastern regions of the country. This underscores the imperative need to control the spread of the disease. The methods utilized to conduct quality control for food associated with outbreaks and to assess the potential for the oral transmission of CD through consuming açaí primarily rely on isolating the parasite or inoculating food into experimental animals, restricting the analyses to major research centers. While there are existing studies in the literature on the detection and quantification of T. cruzi DNA in açaí, the evaluation of parasites' viability using molecular methods in this type of sample and differentiating between live and dead parasites in açaí pulp remain challenging. Consequently, we developed a molecular methodology based on RT-qPCR for detecting and quantifying viable T. cruzi in açaí pulp samples. This protocol enables the stabilization and preservation of nucleic acids in açaí, along with incorporating an exogenous internal amplification control. The standardization of the RNA extraction method involved a simple and reproducible approach, coupled with a one-step RT-qPCR assay. The assay underwent validation with various T. cruzi DTUs and demonstrated sensitivity in detecting up to 0.1 viable parasite equivalents/mL in açaí samples. Furthermore, we investigated the effectiveness of a bleaching method in eliminating viable parasites in açaí samples contaminated with T. cruzi by comparing the detection of DNA versus RNA. Finally, we validated this methodology using açaí pulp samples positive for T. cruzi DNA, which were collected in a municipality with a history of oral CD outbreaks (Coari-AM). This validation involved comparing the detection and quantification of total versus viable T. cruzi. Collectively, our findings demonstrate the feasibility of this methodology in detecting viable forms of T. cruzi in açaí pulp samples, emerging as a crucial tool for monitoring oral outbreaks of Chagas disease resulting from açaí consumption.


Subject(s)
Chagas Disease , Trypanosoma cruzi , Trypanosoma cruzi/genetics , Trypanosoma cruzi/isolation & purification , Chagas Disease/epidemiology , Chagas Disease/parasitology , Chagas Disease/transmission , Chagas Disease/diagnosis , Animals , Real-Time Polymerase Chain Reaction/methods , Euterpe , Brazil/epidemiology , Humans , DNA, Protozoan/genetics
12.
Molecules ; 29(10)2024 May 09.
Article in English | MEDLINE | ID: mdl-38792079

ABSTRACT

Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.


Subject(s)
Amide Synthases , Glutathione , NADH, NADPH Oxidoreductases , Trypanosoma , NADH, NADPH Oxidoreductases/metabolism , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Humans , Amide Synthases/metabolism , Amide Synthases/antagonists & inhibitors , Trypanosoma/drug effects , Trypanosoma/metabolism , Glutathione/metabolism , Glutathione/analogs & derivatives , Animals , Spermidine/analogs & derivatives , Spermidine/metabolism , Leishmania/drug effects , Leishmania/metabolism , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Leishmaniasis/drug therapy , Leishmaniasis/metabolism , Leishmaniasis/parasitology , Trypanosomatina/metabolism , Trypanosomatina/drug effects , Protozoan Proteins/metabolism , Protozoan Proteins/antagonists & inhibitors , Chagas Disease/drug therapy , Chagas Disease/parasitology , Chagas Disease/metabolism
13.
PLoS Negl Trop Dis ; 18(5): e0012199, 2024 May.
Article in English | MEDLINE | ID: mdl-38776344

ABSTRACT

BACKGROUND: In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. METHODOLOGY/PRINCIPAL FINDINGS: In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. CONCLUSION/SIGNIFICANCE: We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.


Subject(s)
Astrocytes , Chagas Disease , Fluoxetine , Mice, Inbred C57BL , Serotonin , Trypanosoma cruzi , Animals , Fluoxetine/pharmacology , Fluoxetine/therapeutic use , Chagas Disease/drug therapy , Chagas Disease/psychology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/physiology , Serotonin/metabolism , Mice , Astrocytes/drug effects , Disease Models, Animal , Brain/drug effects , Brain/parasitology , Brain/metabolism , Behavior, Animal/drug effects , Male , Humans , Selective Serotonin Reuptake Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Cognition/drug effects , Depression/drug therapy , Parasite Load , Anxiety/drug therapy
14.
Adv Clin Chem ; 120: 169-190, 2024.
Article in English | MEDLINE | ID: mdl-38762241

ABSTRACT

Developing molecular strategies to manipulate gene expression in trypanosomatids is challenging, particularly with respect to the unique gene expression mechanisms adopted by these unicellular parasites, such as polycistronic mRNA transcription and multi-gene families. In the case of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas Disease, the lack of RNA interference machinery further complicated functional genetic studies important for understanding parasitic biology and developing biomarkers and potential therapeutic targets. Therefore, alternative methods of performing knockout and/or endogenous labelling experiments were developed to identify and understand the function of proteins for survival and interaction with the host. In this review, we present the main tools for the genetic manipulation of T. cruzi, focusing on the Clustered Regularly Interspaced Short Palindromic Repeats Cas9-associated system technique widely used in this organism. Moreover, we highlight the importance of using these tools to elucidate the function of uncharacterized and glycosylated proteins. Further developments of these technologies will allow the identification of new biomarkers, therapeutic targets and potential vaccines against Chagas disease with greater efficiency and speed.


Subject(s)
Gene Expression Regulation , Trypanosoma cruzi , Trypanosoma cruzi/genetics , Trypanosoma cruzi/metabolism , Humans , Chagas Disease , CRISPR-Cas Systems , Animals , Protozoan Proteins/genetics , Protozoan Proteins/metabolism
16.
Rev Bras Epidemiol ; 27: e240020, 2024.
Article in English, Portuguese | MEDLINE | ID: mdl-38775617

ABSTRACT

OBJECTIVE: To analyze the survival of patients with Chagas disease, beneficiaries of social security and social assistance, in Brazil, from 1942 to 2016. METHODS: This is a retrospective cohort study with data from the Brazilian Ministry of Social Security. The event of interest was death, and the survival functions were estimated by the Kaplan-Meier and Cox regression methods. RESULTS: In the period "onset of the disease until death", women (HR=0.54; 95%CI 0.43-0.53) and receiving social security benefits (HR=0.13; 95%CI 0.11-0.23) were associated with longer survival. Lower survival was associated with the cardiac form of the disease (HR=2.64; 95%CI 2.23-3.12), living in a rural area (HR=1.23; 95%CI 1.14-1.21), and manifestation of the disease between the years 2000 and 2016 (HR=5.32; 95%CI 4.74-5.93). Likewise, in the period "work disability until death", women (HR=0.51; 95%CI 0.41-0.52) and receiving social security benefits (HR=0.24; 95%CI 0,14-0.45) were associated with longer survival, as well as the cardiac form of the disease (HR=1.95; 95%CI 1.83-2.13), living in a rural area (HR=1.31; 95%CI 1.21-1.54), and manifestation of the disease between 2000 and 2016 (HR=1.53; 95%CI 1.33-1.71) were associated with lower survival. CONCLUSION: The main predictors of mortality and survival of patients with Chagas disease who receive social security and assistance benefits in Brazil were presented. These findings can guide the definition of priorities for follow-up actions by Primary Health Care, currently recommended for the longitudinal management of the disease.


Subject(s)
Chagas Disease , Social Security , Humans , Brazil/epidemiology , Social Security/statistics & numerical data , Female , Male , Retrospective Studies , Chagas Disease/mortality , Adult , Middle Aged , Young Adult , Adolescent , Aged , Survival Analysis , Child , Kaplan-Meier Estimate , Child, Preschool , Infant , Time Factors , Proportional Hazards Models , Sex Distribution
17.
Circ Res ; 134(10): 1379-1397, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38723031

ABSTRACT

Chagas cardiomyopathy caused by infection with the intracellular parasite Trypanosoma cruzi is the most common and severe expression of human Chagas disease. Heart failure, systemic and pulmonary thromboembolism, arrhythmia, and sudden cardiac death are the principal clinical manifestations of Chagas cardiomyopathy. Ventricular arrhythmias contribute significantly to morbidity and mortality and are the major cause of sudden cardiac death. Significant gaps still exist in the understanding of the pathogenesis mechanisms underlying the arrhythmogenic manifestations of Chagas cardiomyopathy. This article will review the data from experimental studies and translate those findings to draw hypotheses about clinical observations. Human- and animal-based studies at molecular, cellular, tissue, and organ levels suggest 5 main pillars of remodeling caused by the interaction of host and parasite: immunologic, electrical, autonomic, microvascular, and contractile. Integrating these 5 remodeling processes will bring insights into the current knowledge in the field, highlighting some key features for future management of this arrhythmogenic disease.


Subject(s)
Arrhythmias, Cardiac , Chagas Cardiomyopathy , Humans , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/parasitology , Arrhythmias, Cardiac/physiopathology , Chagas Cardiomyopathy/parasitology , Trypanosoma cruzi/pathogenicity , Chagas Disease/complications , Chagas Disease/parasitology , Chagas Disease/immunology
18.
Parasit Vectors ; 17(1): 240, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38802953

ABSTRACT

BACKGROUND: Chagas disease, caused by Trypanosoma cruzi, is still a public health problem in Latin America and in the Southern Cone countries, where Triatoma infestans is the main vector. We evaluated the relationships among the density of green vegetation around rural houses, sociodemographic characteristics, and domestic (re)infestation with T. infestans while accounting for their spatial dependence in the municipality of Pampa del Indio between 2007 and 2016. METHODS: The study comprised sociodemographic and ecological variables from 734 rural houses with no missing data. Green vegetation density surrounding houses was estimated by the normalized difference vegetation index (NDVI). We used a hierarchical Bayesian logistic regression composed of fixed effects and spatial random effects to estimate domestic infestation risk and quantile regressions to evaluate the association between surrounding NDVI and selected sociodemographic variables. RESULTS: Qom ethnicity and the number of poultry were negatively associated with surrounding NDVI, whereas overcrowding was positively associated with surrounding NDVI. Hierarchical Bayesian models identified that domestic infestation was positively associated with surrounding NDVI, suitable walls for triatomines, and overcrowding over both intervention periods. Preintervention domestic infestation also was positively associated with Qom ethnicity. Models with spatial random effects performed better than models without spatial effects. The former identified geographic areas with a domestic infestation risk not accounted for by fixed-effect variables. CONCLUSIONS: Domestic infestation with T. infestans was associated with the density of green vegetation surrounding rural houses and social vulnerability over a decade of sustained vector control interventions. High density of green vegetation surrounding rural houses was associated with households with more vulnerable social conditions. Evaluation of domestic infestation risk should simultaneously consider social, landscape and spatial effects to control for their mutual dependency. Hierarchical Bayesian models provided a proficient methodology to identify areas for targeted triatomine and disease surveillance and control.


Subject(s)
Chagas Disease , Insect Vectors , Triatoma , Triatoma/physiology , Triatoma/parasitology , Animals , Chagas Disease/transmission , Chagas Disease/epidemiology , Humans , Argentina/epidemiology , Insect Vectors/physiology , Bayes Theorem , Rural Population , Trypanosoma cruzi , Housing , Socioeconomic Factors , Risk Factors
19.
Amino Acids ; 56(1): 35, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698213

ABSTRACT

Chagas disease, caused by the protozoa Trypanosoma cruzi, continues to be a serious public health problem in Latin America, worsened by the limitations in its detection. Given the importance of developing new diagnostic methods for this disease, the present review aimed to verify the number of publications dedicated to research on peptides that demonstrate their usefulness in serodiagnosis. To this end, a bibliographic survey was conducted on the PubMed platform using the keyword "peptide" or "epitope" combined with "Chagas disease" or "Trypanosoma cruzi"; "diagno*" or "serodiagnosis" or "immunodiagnosis", without period restriction. An increasing number of publications on studies employing peptides in ELISA and rapid tests assays was verified, which confirms the expansion of research in this field. It is possible to observe that many of the peptides tested so far originate from proteins widely used in the diagnosis of Chagas, and many of them are part of commercial tests developed. In this sense, as expected, promising results were obtained for several peptides when tested in ELISA, as many of them exhibited sensitivity and specificity values above 90%. Furthermore, some peptides have been tested in several studies, confirming their diagnostic potential. Despite the promising results observed, it is possible to emphasize the need for extensive testing of peptides, using different serological panels, in order to confirm their potential. The importance of producing an effective assay capable of detecting the clinical stages of the disease, as well as new immunogenic antigens that enable new serological diagnostic tools for Chagas disease, is evident.


Subject(s)
Chagas Disease , Enzyme-Linked Immunosorbent Assay , Peptides , Trypanosoma cruzi , Chagas Disease/diagnosis , Chagas Disease/immunology , Chagas Disease/blood , Humans , Trypanosoma cruzi/immunology , Peptides/immunology , Peptides/chemistry , Enzyme-Linked Immunosorbent Assay/methods , Immunologic Tests/methods , Antigens, Protozoan/immunology , Antigens, Protozoan/blood , Serologic Tests/methods
20.
Internet resource in Portuguese | LIS -Health Information Locator | ID: lis-49600

ABSTRACT

O declínio dos títulos de anticorpos específicos para o Trypanosoma cruzi, em pacientes com diagnóstico de doença de Chagas crônica após o tratamento, foi avaliado em estudo, utilizando proteínas quiméricas. A pesquisa, de coorte transversal prospectiva envolveu participantes com diagnóstico positivo para T. cruzi, da região de Añatuya, na Argentina, e que foram tratados com benznidazol.


Subject(s)
Chagas Disease/prevention & control , Recombinant Fusion Proteins
SELECTION OF CITATIONS
SEARCH DETAIL
...