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1.
PLoS Negl Trop Dis ; 14(8): e0008529, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804966

RESUMO

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.


Assuntos
Cardiomiopatias , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/uso terapêutico , Adulto , Bases de Dados Factuais , Humanos , Nifurtimox/uso terapêutico , Segurança do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triazóis/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos
2.
PLoS Negl Trop Dis ; 14(8): e0008411, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776929

RESUMO

Approximately 150 triatomine species are suspected to be infected with the Chagas parasite, Trypanosoma cruzi, but they differ in the risk they pose to human populations. The largest risk comes from species that have a domestic life cycle and these species have been targeted by indoor residual spraying campaigns, which have been successful in many locations. It is now important to consider residual transmission that may be linked to persistent populations of dominant vectors, or to secondary or minor vectors. The aim of this project was to define the geographical distributions of the community of triatomine species across the Chagas endemic region. Presence-only data with over 12, 000 observations of triatomine vectors were extracted from a public database and target-group background data were generated to account for sampling bias in the presence data. Geostatistical regression was then applied to estimate species distributions and fine-scale distribution maps were generated for thirty triatomine vector species including those found within one or two countries and species that are more widely distributed from northern Argentina to Guatemala, Bolivia to southern Mexico, and Mexico to the southern United States of America. The results for Rhodnius pictipes, Panstrongylus geniculatus, Triatoma dimidiata, Triatoma gerstaeckeri, and Triatoma infestans are presented in detail, including model predictions and uncertainty in these predictions, and the model validation results for each of the 30 species are presented in full. The predictive maps for all species are made publicly available so that they can be used to assess the communities of vectors present within different regions of the endemic zone. The maps are presented alongside key indicators for the capacity of each species to transmit T. cruzi to humans. These indicators include infection prevalence, evidence for human blood meals, and colonisation or invasion of homes. A summary of the published evidence for these indicators shows that the majority of the 30 species mapped by this study have the potential to transmit T. cruzi to humans.


Assuntos
Insetos Vetores , Triatominae/parasitologia , Trypanosoma cruzi , Distribuição Animal , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/transmissão , Habitação , Humanos , América Latina/epidemiologia , Modelos Teóricos
3.
PLoS Negl Trop Dis ; 14(8): e0008402, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797041

RESUMO

A Trypanosoma cruzi Loopamp kit was recently developed as a ready-to-use diagnostic method requiring minimal laboratory facilities. We evaluated its diagnostic accuracy for detection of acute Chagas disease (CD) in different epidemiological and clinical scenarios. In this retrospective study, a convenience series of clinical samples (venous blood treated with EDTA or different stabilizer agents, heel-prick blood in filter paper or cerebrospinal fluid samples (CSF)) from 30 infants born to seropositive mothers (13 with congenital CD and 17 noninfected), four recipients of organs from CD donors, six orally-infected cases after consumption of contaminated guava juice and six CD patients coinfected with HIV at risk of CD reactivation (N = 46 patients, 46 blood samples and 1 CSF sample) were tested by T. cruzi Loopamp kit (Tc LAMP) and standardized quantitative real-time PCR (qPCR). T. cruzi Loopamp accuracy was estimated using the case definition in the different groups as a reference. Cohen's kappa coefficient (κ) was applied to measure the agreement between Tc LAMP (index test) and qPCR (reference test). Sensitivity and specificity of T. cruzi Loopamp kit in blood samples from the pooled clinical groups was 93% (95% CI: 77-99) and 100% (95% CI: 80-100) respectively. The agreement between Tc LAMP and qPCR was almost perfect (κ = 0.92, 95% CI: 0.62-1.00). The T. cruzi Loopamp kit was sensitive and specific for detection of T. cruzi infection. It was carried out from DNA extracted from peripheral blood samples (via frozen EDTA blood, guanidine hydrochloride-EDTA blood, DNAgard blood and dried blood spots), as well as in CSF specimens infected with TcI or TcII/V/VI parasite populations. The T. cruzi Loopamp kit appears potentially useful for rapid detection of T. cruzi infection in congenital, acute and CD reactivation due to HIV infection.


Assuntos
Doença de Chagas/sangue , Doença de Chagas/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Trypanosoma cruzi/isolamento & purificação , Doença de Chagas/líquido cefalorraquidiano , Doença de Chagas/congênito , Coinfecção , DNA de Protozoário/análise , Feminino , Infecções por HIV , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Sensibilidade e Especificidade , Transplantados , Trypanosoma cruzi/fisiologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-32844905

RESUMO

This study aimed to describe the spatial distribution and assess entomological indicators of synanthropic triatomines in Piaui State, Northeastern Brazil. We used surveillance data on the detection, identification and assessment of natural infection with trypanosomatids from triatomines in the State from 2014 to 2017. The State was divided into four macroregions. In relation to the dispersion rates of triatomines, they were much lower in the North, when compared to Southwest, Southeast and Central North macroregions. Infestation rates were higher in the Southwest and Southeast and intradomicile infestation rates varied during the study period, reaching high values in all regions. Insects belonging to the species Triatoma brasiliensis complex, Triatoma pseudomaculata, Triatoma sordida, and to the genus Panstrongylus spp. and Rhodnius spp. were collected during this period. T. brasiliensis was collected from all four regions of the State, but more frequently in those located in the Southeast. A similar pattern was observed for T. pseudomaculata. T. sordida was detected in the municipalities in the Southeast and Southwest regions, and less frequently in the Central North municipalities. Rhodnius spp. was detected in the Central North and North regions, and Panstrongylus spp. in the Central North and Southeast regions. The highest trypanosomatid-positivity rate of T. brasiliensis and Panstrongylus spp. was in the Southeast region. A significant proportion of the municipalities of Piaui State presents entomological parameters that indicate a risk of Chagas disease by vector transmission.


Assuntos
Doença de Chagas , Insetos Vetores/parasitologia , Triatoma/parasitologia , Triatominae/classificação , Trypanosoma cruzi/isolamento & purificação , Animais , Brasil , Doença de Chagas/diagnóstico , Doença de Chagas/transmissão , Triatominae/parasitologia
5.
PLoS Negl Trop Dis ; 14(7): e0008487, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716934

RESUMO

New assay designs are needed to improve the predictive value of the Trypanosoma cruzi in vitro tests used as part of the Chagas' disease drug development pipeline. Here, we employed a green fluorescent protein (eGFP)-expressing parasite line and live high-content imaging to monitor the growth of T. cruzi amastigotes in mouse embryonic fibroblasts. A novel assay design allowed us to follow parasite numbers over 6 days, in four-hour intervals, while occupying the microscope for only 24 hours per biological replicate. Dose-response curves were calculated for each time point after addition of test compounds, revealing how EC50 values first decreased over the time of drug exposure, and then leveled off. However, we observed that parasite numbers could vary, even in the untreated controls, and at different sites in the same well, which caused variability in the EC50 values. To overcome this, we established that fold change in parasite number per hour is a more robust and informative measure of drug activity. This was calculated based on an exponential growth model for every biological sample. The net fold change per hour is the result of parasite replication, differentiation, and death. The calculation of this fold change enabled us to determine the tipping point of drug action, i.e. the time point when the death rate of the parasites exceeded the growth rate and the fold change dropped below 1, depending on the drug concentration and exposure time. This revealed specific pharmacodynamic profiles of the benchmark drugs benznidazole and posaconazole.


Assuntos
Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Tripanossomicidas/farmacologia , Humanos , Nitroimidazóis/farmacologia , Triazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
6.
Mem Inst Oswaldo Cruz ; 115: e200214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32725060

RESUMO

BACKGROUND Chagas disease, resulting from Trypanosoma cruzi infections, continues to be a health concern mainly in Latin American countries where the parasite is endemic. The laboratory diagnosis of a chronic infection is determined through serological assays for antibodies against T. cruzi and several tests are available that differ in key components, formats and methodologies. To date, no single test meets the criteria of a gold standard. The situation is further complicated by the difficulties associated with performance comparisons between different immunoassays or methodologies executed at different times and geographical areas. OBJECTIVE To improve the diagnosis of Chagas disease, the WHO coordinated the development of two International Biological Reference Standards for antibodies against anti-T. cruzi: NIBSC 09/186 and NIBSC 09/188 that respectively represent geographical regions with the highest prevalence of TcII and TcI lineages of the parasite. METHODS The principle goal of this study was to verify the behavior of these standards when assayed by several commercially available serological tests that employ different methods to capture and detect human anti-T. cruzi antibodies. FINDINGS AND MAIN CONCLUSIONS The results reinforce the recommendation that these standards be considered for performance evaluations of commercialised immunoassays and should be an integral step in the development of new test components or assay paradigms.


Assuntos
Doença de Chagas/diagnóstico , Testes Sorológicos/normas , Trypanosoma cruzi/isolamento & purificação , Anticorpos Antiprotozoários/sangue , Doença de Chagas/parasitologia , Humanos , Imunoensaio/métodos , Padrões de Referência , Testes Sorológicos/métodos , Trypanosoma cruzi/imunologia , Organização Mundial da Saúde
7.
Artigo em Inglês | MEDLINE | ID: mdl-32725057

RESUMO

The present study aimed to review the existing literature and to evaluate the best dose regimen for benznidazole in adult patients with Chagas disease in the chronic phase. A systematic review was conducted followed by meta-analysis. Searches were performed in four databases, to include studies published until May 2019. The descriptors used were: "Chagas disease", "benznidazole", "Drug Therapy", "Pharmacokinetics", "Dose-response relationship, drug" and "Chronic disease". The meta-analysis compared studies using the standard dose of 5 mg/kg/day for 30 or 60 days. A total of 608 articles were found, 23 of which were considered eligible for this review and nine were included in the meta-analysis. The studies selected and analyzed were published between 1996 and 2018, with various benznidazole dose regimens, ranging from 2.5 mg/kg/day to 10 mg/kg/day, for 30 to 80 days of treatment. The results pointed to a great diversity of dose regimens, thus there is no consensus on the optimal dose regimen for benznidazole in the chronic phase of Chagas disease.


Assuntos
Doença de Chagas , Nitroimidazóis , Trypanosoma cruzi , Adulto , Doença de Chagas/tratamento farmacológico , Doença Crônica , Humanos , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem
8.
Rev Chilena Infectol ; 37(2): 129-137, 2020 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-32730478

RESUMO

BACKGROUND: In 2016, the Hospital Dr. Félix Bulnes Cerda (HDFBC) implemented the mandatory screening of anti Trypanosoma cruzi antibodies in pregnant women, thus complying with national regulations to detect new Chagas disease cases (CHD) in mother and child, whose early detection mediates timely pharmacological treatment. This, because the congenital transmission continues the main active transmission mechanisms of T. cruzi and a major public health problem for the country. AIM: To present the epidemiological information generated after the implementation of the ECH screening in the SSFCC HFBC, two years after its operation began. METHODS: Screening test: inmunequimioluminiscence (IQLU), certification by IFI, ELISA and/or western blot. Follow up of newborn infants with PCR, IFI, ELISA and IQLU. RESULTS: Between April 2016 and July 2018, 14.012 subject's samples were examined of which 62 resulted reactive (0.53% seropositivity) in the total studied population where 28 patients resulted positive for CHD, which corresponds to a 0.2% prevalence. Of the total population, 11.780 were pregnant women, of these 41 were reactive and 10 were confirmed with CHD thus showing a prevalence of 0.085%. The other 18 positive cases of non-pregnant patients corresponded a prevalence of 0.81%. Also, 10 newborn and infant children of mothers with CHD were followed up. In all, congenital transmission (0%) was ruled out. Nifurtimox treatment of the mothers were completed in 30% of them. It is concluded that the implementation of the program in the HDFBC fulfills the objectives of screening, detection and diagnosis of CHD, so as the timely follow-up and pharmacologic treatment of the newborn. The 0.085% prevalence of CHD in pregnant women as the 0.20% in total population are significantly lower (p-valor < 0.01) than the 0.7% reported in 2016 for the Metropolitan Region (MR), a fact that we suggest is a consequence of the national program implementation. Likewise, the 0% transplacental transmission is accorded to the rate of 0.91 x 10.000 live births reported in 2017 for the MR. Based on the learning acquired during the development of the research, recommendations are given to contribute to the operation of the program.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Chile , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Gravidez , Atenção Primária à Saúde
9.
Mem Inst Oswaldo Cruz ; 115: e200019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32696913

RESUMO

BACKGROUND: NME23/NDPKs are well conserved proteins found in all living organisms. In addition to being nucleoside diphosphate kinases (NDPK), they are multifunctional enzymes involved in different processes such as DNA stability, gene regulation and DNA repair among others. TcNDPK1 is the canonical NDPK isoform present in Trypanosoma cruzi, which has nuclease activity and DNA-binding properties in vitro. OBJECTIVES: In the present study we explored the role of TcNDPK1 in DNA damage responses. METHODS: TcNDPK1 was expressed in mutant bacteria and yeasts and over-expressed in epimastigotes. Mutation frequencies, tolerance to genotoxic agents and activity of DNA repair enzymes were evaluated. FINDINGS: Bacteria decreased about 15-folds the spontaneous mutation rate and yeasts were more resistant to hydrogen peroxide and to UV radiation than controls. Parasites overexpressing TcNDPK1 were able to withstand genotoxic stresses caused by hydrogen peroxide, phleomycin and hidroxyurea. They also presented less genomic damage and augmented levels of poly(ADP)ribose and poly(ADP)ribose polymerase, an enzyme involved in DNA repair. MAIN CONCLUSION: These results strongly suggest a novel function for TcNDPK1; its involvement in the maintenance of parasite's genome integrity.


Assuntos
Dano ao DNA , Núcleosídeo-Difosfato Quinase/metabolismo , Trypanosoma cruzi/enzimologia , Reparo do DNA , Núcleosídeo-Difosfato Quinase/genética , Poli(ADP-Ribose) Polimerases , Trypanosoma cruzi/genética
10.
Exp Parasitol ; 216: 107932, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32535113

RESUMO

Neglected tropical diseases, such as Chagas disease caused by the protozoa Trypanosoma cruzi, affect millions of people worldwide but lack effective treatments that are accessible to the entire population, especially patients with the debilitating chronic phase. The recognition of host cells, invasion and its intracellular replicative success are essential stages for progression of the parasite life cycle and the development of Chagas disease. It is predicted that programmed cell death pathways (apoptosis) would be activated in infected cells, either via autocrine secretion or mediated by cytotoxic immune cells. This process should play a key role in resolving infections by hindering the evolutionary success of the parasite. In this research, we performed assays to investigate the role of the lectin galectin-3 (Gal3) in parasite-host signaling pathways. Using cells with endogenous levels of Gal3 compared to Gal3-deficient cells (induced by RNA interference), we demonstrated that T. cruzi mediated the survival pathways and the subverted apoptosis through Gal3 promoting a pro-survival state in infected cells. Infected Gal3-depleted cells showed increased activation of caspase 3 and pro-apoptotic targets, such as poly (ADP-ribose) polymerase (PARP), and lower accumulation of anti-apoptotic proteins, such as c-IAP1, survivin and XIAP. During the early stages of infection, Gal3 translocates from the cytoplasm to the nucleus and must act in survival pathways. In a murine model of experimental infection, Gal3 knockout macrophages showed lower infectivity and viability. In vivo infection revealed a lower parasitemia and longer survival and an increased spleen cellularity in Gal3 knockout mice with consequences on the percentage of T lymphocytes (CD4+ CD11b+) and macrophages. In addition, cytokines such as IL-2, IL-4, IL-6 and TNF-α are increased in Gal3 knockout mice when compared to wild type genotype. These data demonstrate a Gal3-mediated complex interplay in the host cell, keeping infected cells alive long enough for infection and intracellular proliferation of new parasites. However, a continuous knowledge of these signaling pathways should contribute to a better understanding the mechanisms of cell death subversion that are promoted by protozoans in the pathophysiology of neglected diseases such as Chagas disease.


Assuntos
Apoptose/fisiologia , Doença de Chagas/parasitologia , Galectina 3/fisiologia , Trypanosoma cruzi/fisiologia , Análise de Variância , Animais , Western Blotting , Caspase 3/análise , Sobrevivência Celular , Doença de Chagas/mortalidade , Chlorocebus aethiops , Colorimetria , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Galectina 3/análise , Galectina 3/genética , Células HeLa , Humanos , Imunofenotipagem , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia/mortalidade , Parasitemia/parasitologia , Fenótipo , Baço/patologia , Células Vero
11.
Artigo em Inglês | PAHO-IRIS | ID: phr-52234

RESUMO

[RESUMEN]. Introducción. La enfermedad de Chagas o tripanosomiasis americana es causada por el protozoo flagelado Trypanosoma cruzi, transmitido principalmente por insectos vectores (denominados popularmente en las diferentes zonas de la Región de las Américas “vinchucas”, “pitos”, “chinches”, “chirimachas” o “kissing bugs”). El parásito es transmitido por vía transplacentaria, transfusiones y, menos frecuentemente, por vía oral o trasplante de órganos. La implementación de políticas públicas y el manejo de la condición clínica requiere ser fortalecido debido a las dificultades diagnósticas y terapéuticas que presenta esta parasitosis sistémica. Para contribuir con ello, la Organización Panamericana de la Salud (OPS) desarrolló una guía para el manejo de la tripanosomiasis americana. Objetivos. Sintetizar las recomendaciones incluidas en la Guía para el diagnóstico y el tratamiento de la enfermedad de Chagas, publicada por la Organización Panamericana de la Salud en 2018, con el fin de presentar el adecuado diagnóstico y tratamiento de la enfermedad de Chagas y abordar aspectos sobre su implementación. Métodos. Se llevó a cabo una síntesis de la guía y sus recomendaciones. Adicionalmente, se realizó una búsqueda sistemática en PubMed, Lilacs, Health Systems Evidence, Epistemonikos y literatura gris de estudios desarrollados en las Américas con el fin de identificar barreras, facilitadores y estrategias de implementación. Resultados. Se presentan 10 recomendaciones aplicables a pacientes adultos y pediátricos con sospecha de enfermedad de Chagas, exposición a T. cruzi y diagnóstico confirmado de enfermedad de Chagas aguda, crónica y congénita. Se identificaron reportes que abordaron aspectos de implementación. Conclusiones. Las recomendaciones buscan proveer estrategias para el diagnóstico y tratamiento oportunos de la enfermedad de Chagas, así como consideraciones para su implementación.


[ABSTRACT]. Introduction. Chagas disease or American trypanosomiasis is caused by the flagellate protozoan Trypanosoma cruzi, transmitted mainly by insect vectors (popularly known in the different areas of the Region of the Americas as “kissing bugs”, “pitos”, “chinches”, or “chirimachas” or “vinchuchas”). The parasite is transmitted via the placenta and in transfusions, and less frequently, orally or during organ transplantation. Because it was necessary to strengthen the implementation of public policies and the management of clinical conditions, given the diagnostic and therapeutic difficulties that this systemic parasitosis presents, the Pan American Health Organization (PAHO) developed guidance for the management of American trypanosomiasis. Objectives. Synthesize the recommendations included in the Guide for Diagnosis and Treatment of Chagas Disease, published (in Spanish only) by the Pan American Health Organization in 2018, in order to present the proper diagnostic methods and treatment for Chagas disease and to address aspects of its implementation. Methods. A summary was made of the guide and its recommendations. In addition, a systematic search was conducted in PubMed, Lilacs, Health Systems Evidence, Epistemonikos, and the gray literature for studies carried out in the Americas, in order to identify barriers, facilitators, and implementation strategies. Results. Ten recommendations are made. These are applicable to adult and pediatric patients with suspected Chagas disease, exposure to T. cruzi, or a confirmed diagnosis of acute, chronic, or congenital Chagas disease. Reports that addressed aspects of implementation were identified. Conclusions. The recommendations seek to provide strategies for the timely diagnosis and treatment of Chagas disease, as well as considerations for the implementation of such strategies.


[RESUMO]. Introdução. A doença de Chagas (ou tripanossomíase americana) é uma infecção causada pelo protozoário flagelado Trypanosoma cruzi, comumente transmitido por insetos vetores (popularmente conhecidos na Região das Américas como “barbeiro”, ‘’chupão’’, ‘’vinchuca’’, “pito”, “chinche”, “chirimacha” ou “kissing bug”). O parasita é transmitido por via transplacentária, transfusão de sangue e, menos comumente, por via oral ou transplante de órgãos de doadores infectados. A implementação de políticas públicas e o manejo clínico devem ser reforçados diante das dificuldades de diagnóstico e terapêutica para esta doença parasitária sistêmica. Em apoio a este propósito, a Organização Pan-Americana da Saúde (OPAS) elaborou um guia para o manejo da doença de Chagas. Objetivos. Sintetizar as recomendações contidas no Guía para el diagnóstico y el tratamiento de la enfermedad de Chagas (guia de diagnóstico e tratamento da doença de Chagas, disponível apenas em espanhol), publicado pela Organização Pan-Americana da Saúde em 2018, com o propósito de apresentar o diagnóstico e o tratamento adequados da doença de Chagas e abordar aspectos relativos à implementação. Métodos. Foi realizada uma síntese do guia e das recomendações apresentadas. Foi também conduzida uma busca sistemática nas bases de dados PubMed, LILACS, Health Systems Evidence e Epistemonikos e na literatura cinzenta de estudos realizados na Região das Américas visando identificar barreiras, facilitadores e estratégias de implementação. Resultados. O guia oferece 10 recomendações para pacientes adultos e pediátricos com suspeita de doença de Chagas, exposição ao T. cruzi e diagnóstico confirmado de doença de Chagas aguda, crônica e congênita e discute aspectos relativos à implementação. Conclusões. As recomendações visam fornecer estratégias para o diagnóstico e o tratamento de forma oportuna da doença de Chagas e são feitas considerações para a implementação destas estratégias.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Medicina Baseada em Evidências , Doenças Parasitárias , Diagnóstico , Terapêutica , América , Doença de Chagas , Medicina Baseada em Evidências , Doenças Parasitárias , Diagnóstico , Terapêutica , América , Doença de Chagas , Medicina Baseada em Evidências , Doenças Parasitárias , Terapêutica
12.
Mol Immunol ; 124: 51-60, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526557

RESUMO

American Trypanosomiasis, a parasitic disease produced by Trypanosoma cruzi (T. cruzi), endemic in Latin America, infects about 6 million people. During the chronic stage of the infection, approximately 30% of infected people will develop Chagas Disease, the clinical manifestation. Few decades ago it was reported that, during the chronic stage, the parasite interferes with the development of solid tumors. However, the identification of parasite molecules responsible for such effects remained elusive. Years later, we described T.cruzi Calreticulin (TcCalr), an endoplasmic reticulum resident chaperone that infective trypomastigotes translocate to the parasite exterior, where it displays anticomplement activities. Most likely, at least some of these activities are related with the antitumor properties of TcCalr, as shown in in vitro, ex vivo, in ovum, and in vivo models. In this context we, we have seen that in vivo subcutaneous peritumoral inoculation of rTcCalr enhances local infiltration of T cells and slows tumor development. Based on these precedents, we propose that in vitro treatment of a mammary adenocarcinoma (TA3 cell line) with rTcCalr, will enhance tumor immunogenicity. In agreement with this proposal, we have shown that: i). rTcCalr binds to TA3 cells in a concentration-dependent fashion, ii). C1q binds to TA3 cells in an rTcCalr-dependent fashion, confirmed by the reversion attained using anti-TcS (a central TcCalr domain that binds C1) F(ab')2 antibody fragments, iii). incubation of TA3 cells with rTcCalr, promotes cell phagocytosis by murine macrophages and, iv). rTcCalr decreases the membrane expression of MHC class II, m-Dectin-1, Galectin-9 and PD-L1, while increasing the expression of Rae-1γ. In synthesis, herein we show that in vitro treatment of a murine mammary adenocarcinoma with rTcCalr enhances phagocytosis and modulates the expression of a variety of membrane molecules that correlates with increased tumor immunogenicity.


Assuntos
Adenocarcinoma/imunologia , Antígenos de Protozoários/imunologia , Calreticulina/imunologia , Neoplasias Mamárias Experimentais/imunologia , Animais , Linhagem Celular Tumoral , Camundongos , Fagocitose/imunologia , Trypanosoma cruzi
13.
PLoS Negl Trop Dis ; 14(6): e0008311, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497037

RESUMO

BACKGROUND: Trypanosoma cruzi has a high genetic and biological diversity and has been subdivided into seven genetic lineages, named TcI-TcVI and TcBat. DTUs TcI-TcII-TcV and TcVI are agents of ChD in different regions of Latin America. Due to population movements, the disease is an emergent global public health problem. Thus, the aim of this study was to quantify the parasitic load and identify the presence of T. cruzi DTUs in 101 Latin American immigrants with chronic ChD, residing in Barcelona, Spain. METHODOLOGY / PRINCIPAL FINDINGS: 5ml of peripheral blood were collected in guanidine/EDTA from each patient for DNA extraction, quantification of the parasitic load and genotyping. A great variation of the parasitic load of the patients was verified: from 0.001 to 22.2 T. cruzi DNA (fg) / Blood DNA (ng). In patients from Bolivia the parasitic load was 3.76±4.43 T. cruzi DNA (fg) / Blood DNA (ng) (mean ± SD), in patients of other countries was 0.95±1.38 T. cruzi DNA (fg) / Blood DNA (ng). No statistically significant difference was observed in the parasitic load between patients with the indeterminate and cardiac forms of ChD (p = 0,57). Parasite genotyping was performed by multilocus conventional PCR. In patients from Bolivia there was a nearly equal prevalence of DTUs TcV (27/77), TcII/TcV/TcVI (26/77), and TcII/TcVI (22/77). TcVI was detected in only 2 samples (2/77). A higher prevalence of TcII/TcVI (19/24) was verified in patients of other countries, with low prevalence of TcII/TcV/TcVI (4/24) and TcV (1/24). CONCLUSIONS/SIGNIFICANCE: In this study, low/medium parasitic load was found in all patients evaluated. Our data corroborate previous conclusions indicating that patients from the Bolivia, living in Spain, are predominantly infected by TcV, and TcVI DTUs. On the other hand, in Non-Bolivians patients TcII/TcVI predominated. Surprisingly, in our cohort of 101 patients no infection by TcI DTU was observed.


Assuntos
Doença de Chagas/etnologia , Doença de Chagas/parasitologia , DNA de Protozoário/genética , Emigrantes e Imigrantes , Trypanosoma cruzi/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Bolívia/etnologia , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Carga Parasitária , Análise de Sequência de DNA , Espanha/epidemiologia , Trypanosoma cruzi/isolamento & purificação , Adulto Jovem
14.
PLoS Negl Trop Dis ; 14(6): e0008398, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32569280

RESUMO

Approximately 300,000 persons in the United States (US) are infected with Trypanosoma cruzi, the protozoan that causes Chagas disease, but less than 1% are estimated to have received antiparasitic treatment. Benznidazole was approved by the US Food and Drug Administration (FDA) for treatment of T. cruzi infection in 2017 and commercialized in May 2018. This paper analyzes factors that affect access to benznidazole following commercialization and suggests directions for future actions to expand access. We applied an access framework to identify barriers, facilitators, and key actors that influence the ability of people with Chagas disease to receive appropriate treatment with benznidazole. Data were collected from the published literature, key informants, and commercial databases. We found that the mean number of persons who obtained benznidazole increased from just under 5 when distributed by the CDC to 13 per month after the commercial launch (from May 2018 to February 2019). Nine key barriers to access were identified: lack of multi-sector coordination, failure of health care providers to use a specific order form, lack of an emergency delivery system, high medical costs for uninsured patients, narrow indications for use of benznidazole, lack of treatment guidelines, limited number of qualified treaters, difficulties for patients to make medical appointments, and inadequate evaluation by providers to determine eligibility for treatment. Our analysis shows that access to benznidazole is still limited after FDA approval. We suggest six areas for strategic action for the pharmaceutical company that markets benznidazole and its allied private foundation to expand access to benznidazole in the US. In addition, we recommend expanding the existing researcher-clinician network by including government agencies, companies and others. This paper's approach could be applied to access programs for benznidazole in other countries or for other health products that target neglected populations throughout the world.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/provisão & distribução , Nitroimidazóis/uso terapêutico , Tripanossomicidas/provisão & distribução , Tripanossomicidas/uso terapêutico , Fatores Etários , Centers for Disease Control and Prevention, U.S. , Custos de Medicamentos , Drogas em Investigação , Humanos , Nitroimidazóis/economia , Tripanossomicidas/economia , Trypanosoma cruzi , Estados Unidos , United States Food and Drug Administration
15.
PLoS Negl Trop Dis ; 14(6): e0008414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574175

RESUMO

Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Movimento Celular , Doença de Chagas/parasitologia , Citoplasma/metabolismo , Citoplasma/parasitologia , Modelos Animais de Doenças , Feminino , Coração , Controle de Infecções , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia
16.
Am J Trop Med Hyg ; 103(1): 428-436, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32458775

RESUMO

Trypanosoma cruzi is the etiological agent of Chagas disease that infects more than seven million people in Latin America. The parasite is transmitted by triatomine insects, of which some species are often associated with palms. The establishment of oil palm plantations (Elaeis guineensis) in the Orinoco region (Colombia) has been rapidly growing, possibly constituting a new environment for the establishment and increase in triatomine populations. In this study, the potential of Rhodnius prolixus to colonize E. guineensis plantations and maintain T. cruzi transmission was assessed. Fieldwork was conducted in two areas located in the department of Casanare for sampling E. guineensis and Attalea butyracea palms, sampling for triatomines to determine their abundance and prevalence of T. cruzi infection. To assess T. cruzi transmission potential in the area, sylvatic and domestic mammals were sampled. Results showed that palm infestation with triatomines was higher in A. butyracea than in E. guineensis palms and T. cruzi infection in triatomines varied between habitats for one study area, but was constant in the other site. Trypanosoma cruzi-infected mammals in the E. guineensis plantations were mainly generalist rodents, suggesting that these mammals could have an important role in T. cruzi transmission in plantations. In conclusion, E. guineensis plantations in the Orinoco region are suitable habitats for R. prolixus and T. cruzi transmission.


Assuntos
Arecaceae , Doença de Chagas/veterinária , Insetos Vetores/parasitologia , Rhodnius/parasitologia , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Quirópteros/parasitologia , Colômbia/epidemiologia , Cães/parasitologia , Florestas , Gambás/parasitologia , Óleo de Palmeira , Roedores/parasitologia , Sus scrofa/parasitologia , Trypanosoma cruzi
17.
Infect Dis Poverty ; 9(1): 51, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393333

RESUMO

BACKGROUND: Chagas disease is endemic in Latin America and still represents an important public health problem in the region. Chronic cardiomyopathy is the most significant chronic form due to its association with morbidity and mortality. The last decade has seen increasing evidence that inflammatory cytokines and chemokines are responsible for the generation of inflammatory infiltrate and tissue damage, with chronic chagasic cardiomyopathy patients presenting a pro-inflammatory immune response. Although studies have evaluated the role of chemokines in experimental T. cruzi infection, few have addressed their systemic profile, especially for human infection and in aging populations. The present work aimed to use the data from a large population based study of older adults, conducted in an endemic area for Chagas disease, to examine the association between serum levels of cytokines and chemokines, T. cruzi infection and electrocardiogram (ECG) abnormality. METHODS: The present work evaluated serum levels of CCL2, CXCL9, CXCL10, CCL5, CXCL8, IL-1ß, IL-6, TNF, IL-12 and IL-10 by Flow Cytometric Bead Array assay (CBA) and the results expressed in pg/ml. The baseline survey started in January 1st 1997, with 1284 participants of an aged population-based cohort. Participants signed an informed consent at baseline and at each subsequent visit and authorized death certificate and medical records verification. RESULTS: Our results demonstrated that Chagas disease patients had higher serum levels of CXCL9, CXCL10 and IL-1ß and lower serum levels of CCL5 than non-infected subjects. Moreover, our data demonstrated that CXCL9 and CXCL10 increased in an age-dependent profile in Chagas disease patients. CONCLUSION: Together, this study provided evidences that serum biomarkers increase along the age continuum and may have potential implications for establishing clinical management protocols and therapeutic intervention in Chagas disease patients.


Assuntos
Envelhecimento , Doença de Chagas/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Trypanosoma cruzi/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Brasil , Estudos de Coortes , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Mem Inst Oswaldo Cruz ; 115: e190457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428081

RESUMO

BACKGROUND Imitation SWItch (ISWI) ATPase is the catalytic subunit in diverse chromatin remodeling complexes. These complexes modify histone-DNA interactions and therefore play a pivotal role in different DNA-dependent processes. In Trypanosoma cruzi, a protozoan that controls gene expression principally post-transcriptionally, the transcriptional regulation mechanisms mediated by chromatin remodeling are poorly understood. OBJECTIVE To characterise the ISWI remodeler in T. cruzi (TcISWI). METHODS A new version of pTcGW vectors was constructed to express green fluorescent protein (GFP)-tagged TcISWI. CRISPR-Cas9 system was used to obtain parasites with inactivated TcISWI gene and we determined TcISWI partners by cryomilling-affinity purification-mass spectrometry (MS) assay as an approximation to start to unravel the function of this protein. FINDINGS Our approach identified known ISWI partners [nucleoplasmin-like protein (NLP), regulator of chromosome condensation 1-like protein (RCCP) and phenylalanine/tyrosine-rich protein (FYRP)], previously characterised in T. brucei, and new components in TcISWI complex [DRBD2, DHH1 and proteins containing a domain characteristic of structural maintenance of chromosomes (SMC) proteins]. Data are available via ProteomeXchange with identifier PXD017869. MAIN CONCLUSIONS In addition to its participation in transcriptional silencing, as it was reported in T. brucei, the data generated here provide a framework that suggests a role for TcISWI chromatin remodeler in different nuclear processes in T. cruzi, including mRNA nuclear export control and chromatin compaction. Further work is necessary to clarify the TcISWI functional diversity that arises from this protein interaction study.


Assuntos
Adenosina Trifosfatases/genética , Montagem e Desmontagem da Cromatina/genética , Fatores de Transcrição/genética , Trypanosoma cruzi/genética , Animais , Western Blotting , Citometria de Fluxo , Regulação da Expressão Gênica
19.
PLoS One ; 15(5): e0232829, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379842

RESUMO

The diagnosis of American tegumentary leishmaniasis (ATL) still requires the design of more effective tools. Leishmania (Viannia) braziliensis is the causal agent of the 90% of Argentinean ATL cases. Considering the current knowledge, an ELISA based crude antigen (CA) for the diagnosis was designed. Ninety-nine subjects diagnosed as ATL, 27 as no-ATL, and 84 donors from non-ATL-endemic areas were included in this study. The current ATL diagnosis was based four techniques, dermal smear microscopic examination (parasitological test), PCR, Leishmanin skin test, and clinical records. We obtained CA extracts from promastigotes and amastigotes from macrophage cultures of different zymodemes of endemic Leishmania species circulating in the study area. Crude antigens from the 'local' main zymodeme of L. (V.) braziliensis showed the highest reactivity against anti-Leishmania antibodies compared to the other included species. The CA of amastigotes of this zymodeme was 3.4 fold more reactive than promastigotes one. Moreover, amastigote-membrane CA (MCA) were 3.6 fold more reactive than the soluble antigens. The MCA-ELISA reached a sensitivity and specificity of 98% (CI = 94.7%-100%) and 63.6% (53.9-73.1), respectively. When anti-Trypanosoma cruzi reactive sera were excluded, the specificity reached 98.4% (94.4-100), while the sensitivity was similar, with a positive predictive value (PV) of 98.6% (94.6-100) and negative PV of 96.3% (91.6-100). The performance of the MCA-ELISA results strongly contribute to the final diagnostic decision, since a non-reactive serological result almost discards the suspected ATL, because of its high negative PV. The developed MCA-ELISA showed a high diagnostic performance, which makes it a good candidate for ATL diagnosis, for seroprevalence studies, or for monitoring treatments efficacy.


Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Membrana Celular/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/diagnóstico , Afinidade de Anticorpos , Especificidade de Anticorpos , Argentina/epidemiologia , Doadores de Sangue , Doenças Endêmicas , Humanos , Leishmania braziliensis/crescimento & desenvolvimento , Leishmaniose Cutânea/sangue , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Mucocutânea/sangue , Leishmaniose Mucocutânea/diagnóstico , Leishmaniose Mucocutânea/parasitologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Trypanosoma cruzi/imunologia
20.
PLoS Negl Trop Dis ; 14(5): e0008262, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32469928

RESUMO

Adhesion of T. cruzi trypomastigotes to components of the extracellular matrix (ECM) is an important step in mammalian host cell invasion. We have recently described a significant increase in the tyrosine nitration levels of histones H2A and H4 when trypomastigotes are incubated with components of the ECM. In this work, we used chromatin immunoprecipitation (ChIP) with an anti-nitrotyrosine antibody followed by mass spectrometry to identify nitrated DNA binding proteins in T. cruzi and to detect alterations in nitration levels induced upon parasite incubation with the ECM. Histone H1, H2B, H2A and H3 were detected among the 9 most abundant nitrated DNA binding proteins using this proteomic approach. One nitrated tyrosine residue (Y29) was identified in Histone H2B in the MS/MS spectrum. In addition, we observed a significant increase in the nitration levels of histones H1, H2B, H2A and H4 upon parasite incubation with ECM. Finally, we used ChIP-Seq to map global changes in the DNA binding profile of nitrated proteins. We observed a significant change in the binding pattern of nitrated proteins to DNA after parasite incubation with ECM. This work provides the first global profile of nitrated DNA binding proteins in T. cruzi and additional evidence for modification in the nitration profile of histones upon parasite incubation with ECM. Our data also indicate that the parasite interaction with the ECM induces alterations in chromatin structure, possibly affecting nuclear functions.


Assuntos
Matriz Extracelular/parasitologia , Histonas/análise , Processamento de Proteína Pós-Traducional , Proteínas de Protozoários/análise , Trypanosoma cruzi/química , Trypanosoma cruzi/crescimento & desenvolvimento , Imunoprecipitação da Cromatina , Matriz Extracelular/metabolismo , Histonas/metabolismo , Espectrometria de Massas , Nitrosação , Proteômica , Proteínas de Protozoários/metabolismo , Tirosina/análogos & derivados , Tirosina/imunologia
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