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1.
Parasitol Res ; 118(9): 2523-2529, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385028

RESUMO

Relatively little is known about the fitness effects and life history trade-offs in medically important parasites and their insect vectors. One such case is the triatomine bugs and the parasite Trypanosoma cruzi, the key actors in Chagas disease. Previous studies have revealed some costs but have not simultaneously examined traits related to development, reproduction, and survival or their possible trade-offs. In addition, these studies have not compared the effects of genetically different T. cruzi strains that differ in their weakening effects in their vertebrate hosts. We compared the body size of the bugs after infection, the number of eggs laid, hatching/non-hatching rate, hatching success, survival, and the resulting number of parasites in Meccus (Triatoma) pallidipennis bugs that were experimentally infected with two strains of T. cruzi (Chilpancingo [CH], the most debilitating in vertebrates; and Morelos [MO], the least debilitating) (both belonging to TcI group). Our results showed that infection affects size (MO < CH; MO and CH = control), number of eggs laid (MO and CH < control) hatching/non-hatching rate (MO < control < CH), hatching success (control < MO, CH = control = MO), and survival (Chilpancingo < Morelos < control). In addition, the CH strain produced more parasites than the MO strain. These results suggest that (a) infection costs depend on the parasite's origin, (b) the more debilitating effects of the CH strain are due to its increased proliferation in the host, and (c) differences in pathogenicity among T. cruzi strains can be maintained through their different effects on hosts' life history traits. Probably, the vectorial capacity mediated by a more aggressive strain could be reduced due to its costs on the triatomine, leading to a lower risk of vertebrate and invertebrate infection in natural populations.


Assuntos
Doença de Chagas/parasitologia , Insetos Vetores/parasitologia , Triatoma/crescimento & desenvolvimento , Triatoma/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Meio Ambiente
2.
Microb Pathog ; 135: 103618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310832

RESUMO

P21 is a protein secreted by Trypanosoma cruzi (T. cruzi). Previous studies have shown a spectrum of biological activities performed by P21 such as induction of phagocytosis, leukocyte chemotaxis and inhibition of angiogenesis. However, the activity of P21 in T. cruzi infection remains unknown. Here, we reported the role of P21 in mice harboring late T. cruzi infection. Treatment with recombinant P21 protein (rP21) reduced parasite load and angiogenesis, and induced fibrosis in the cardiac tissue of infected mice. In addition, rP21 reduced the growth of epimastigotes, inhibited intracellular replication of amastigotes and modulated the parasite cell cycle. Our data suggest that P21 controls parasite replication in the host, supporting the survival of both parasite and host.


Assuntos
Doença de Chagas/imunologia , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Ciclo Celular , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Fibrose , Coração , Interações Hospedeiro-Parasita , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Proteínas de Protozoários/genética , Proteínas Recombinantes , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade
3.
Life Sci ; 232: 116629, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276687

RESUMO

AIMS: To investigate the effects of moderate aerobic physical training on cardiac function and morphology as well as on the levels of glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) of animals infected with the Y strain of Trypanosoma cruzi. MAIN METHODS: Twenty-eight male C57BL/6 mice were distributed into 4 groups: sedentary control (SC), trained control (TC), sedentary infected (CHC) and trained infected (CHT). The infection was performed by intraperitoneal injection of trypomastigote forms and the animals were adapted to treadmill in the week before the beginning of the training protocol, initiated 45 days post infection. Maximal exercise test (TEM) was performed at the baseline as well as at the end of the 4th, 8th and 12th weeks of training. At the end of the 12th week, all animals were evaluated for cardiac morphology and function by echocardiography. KEY FINDINGS: CHC group showed a larger area of right ventricle (RVA), increased end-systolic volume and reduction in ejection fraction (EF), stroke volume (SV), cardiac output (CO) and fractional area change (FAC). The training reduced the RVA and improved the FAC of chagasic animals. GDNF level was higher in TC and CHC groups compared to SC in heart and BDNF levels were higher in CHC compared to SC in heart and serum. SIGNIFICANCE: Physical training ameliorated the cardiac function of infected animals and promoted adjusts in BDNF and GDNF levels. These findings evidenced these neurotrophins as possible biomarkers of cardiac function responsive to exercise stimulus.


Assuntos
Tolerância ao Exercício/fisiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Animais , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/análise , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Débito Cardíaco , Doença de Chagas/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Teste de Esforço , Fator Neurotrófico Derivado de Linhagem de Célula Glial/análise , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Coração/fisiologia , Testes de Função Cardíaca , Ventrículos do Coração/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/análise , Fator de Crescimento Neural/fisiologia , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/fisiologia , Volume Sistólico/fisiologia , Trypanosoma cruzi/patogenicidade
4.
Biomed Res Int ; 2019: 8301569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355283

RESUMO

Chagas disease is a tropical illness caused by the protozoan Trypanosoma cruzi. The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti-T. cruzi effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in T. cruzi. Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Fenotiazinas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Doença de Chagas/parasitologia , Corantes/farmacologia , Humanos , Azul de Metileno/análogos & derivados , Azul de Metileno/farmacologia , Nifurtimox/farmacologia , Nitroimidazóis/farmacologia , Cloreto de Tolônio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/patogenicidade
5.
Acta Trop ; 199: 105057, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31202818

RESUMO

A number of intracellular pathogens are internalized by host cells via multiple endocytic pathways, including Trypanosoma cruzi, the etiological agent of Chagas disease. Clathrin-mediated endocytosis is the most characterized endocytic pathway in mammalian cells. Its machinery was described as being required in mammalian cells for the internalization of large particles, including pathogenic bacteria, fungi, and large virus. To investigate whether T. cruzi entry into host cells can also take advantage of the clathrin-coated vesicle-dependent process, we utilized well-known inhibitors of clathrin-coated vesicle formation (sucrose hypertonic medium, chlorpromazine hydrochloride and pitstop 2) and small interference RNA (siRNA). All treatments drastically reduced the internalization of infective trypomastigotes and amastigotes of T. cruzi by phagocytic (macrophages) and epithelial cells. Clathrin labeling, as observed by fluorescence and electron microscopy, was also observed around the parasites from the initial stages of infection until the complete formation of the parasitophorous vacuole. These unexpected observations suggest the participation of the clathrin pathway in the T. cruzi entry process.


Assuntos
Clatrina/fisiologia , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Clatrina/antagonistas & inibidores , Camundongos , Fagocitose , Células RAW 264.7 , Transdução de Sinais
6.
mBio ; 10(3)2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064825

RESUMO

The mitochondrial Ca2+ uptake in trypanosomatids, which belong to the eukaryotic supergroup Excavata, shares biochemical characteristics with that of animals, which, together with fungi, belong to the supergroup Opisthokonta. However, the composition of the mitochondrial calcium uniporter (MCU) complex in trypanosomatids is quite peculiar, suggesting lineage-specific adaptations. In this work, we used Trypanosoma cruzi to study the role of orthologs for mitochondrial calcium uptake 1 (MICU1) and MICU2 in mitochondrial Ca2+ uptake. T. cruzi MICU1 (TcMICU1) and TcMICU2 have mitochondrial targeting signals, two canonical EF-hand calcium-binding domains, and localize to the mitochondria. Using the CRISPR/Cas9 system (i.e., clustered regularly interspaced short palindromic repeats with Cas9), we generated TcMICU1 and TcMICU2 knockout (-KO) cell lines. Ablation of either TcMICU1 or TcMICU2 showed a significantly reduced mitochondrial Ca2+ uptake in permeabilized epimastigotes without dissipation of the mitochondrial membrane potential or effects on the AMP/ATP ratio or citrate synthase activity. However, none of these proteins had a gatekeeper function at low cytosolic Ca2+ concentrations ([Ca2+]cyt), as occurs with their mammalian orthologs. TcMICU1-KO and TcMICU2-KO epimastigotes had a lower growth rate and impaired oxidative metabolism, while infective trypomastigotes have a reduced capacity to invade host cells and to replicate within them as amastigotes. The findings of this work, which is the first to study the role of MICU1 and MICU2 in organisms evolutionarily distant from animals, suggest that, although these components were probably present in the last eukaryotic common ancestor (LECA), they developed different roles during evolution of different eukaryotic supergroups. The work also provides new insights into the adaptations of trypanosomatids to their particular life styles.IMPORTANCE Trypanosoma cruzi is the etiologic agent of Chagas disease and belongs to the early-branching eukaryotic supergroup Excavata. Its mitochondrial calcium uniporter (MCU) subunit shares similarity with the animal ortholog that was important to discover its encoding gene. In animal cells, the MICU1 and MICU2 proteins act as Ca2+ sensors and gatekeepers of the MCU, preventing Ca2+ uptake under resting conditions and favoring it at high cytosolic Ca2+ concentrations ([Ca2+]cyt). Using the CRISPR/Cas9 technique, we generated TcMICU1 and TcMICU2 knockout cell lines and showed that MICU1 and -2 do not act as gatekeepers at low [Ca2+]cyt but are essential for normal growth, host cell invasion, and intracellular replication, revealing lineage-specific adaptations.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/genética , Adaptação Fisiológica , Transporte Biológico , Sistemas CRISPR-Cas , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte de Cátions , Citosol/química , Citosol/metabolismo , Técnicas de Inativação de Genes , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Protozoários/genética , Trypanosoma cruzi/patogenicidade
7.
Life Sci ; 230: 141-149, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129142

RESUMO

When administered alone, preinfection exercise training and benznidazole-based chemotherapy induce cardioprotection in Chagas disease. However, the effect of concomitant exercise and benznidazole treatment is unknown. We investigated whether exercise and specific chemotherapy could interact to modulate parasitemia, inflammation, redox status and heart damage in a murine model of T. cruzi infection. Wistar rats were randomized into an uninfected control group (CNT) and four groups infected with T. cruzi: sedentary untreated (SUN) and treated (STR), and trained untreated (TUN) and treated (TTR). Running training was administered 5 days/week for 4 weeks. Treated animals concomitantly received 100 mg/kg/day benznidazole. Heart inflammation and reactive damage were not detected in CNT animals. Compared to SUN, TUN animals presented increased levels of parasitemia, myocarditis, nitric oxide, hydrogen peroxide, protein carbonyl, malondialdehyde, cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10 and IL-17), catalase, superoxide dismutase and glutathione reductase activity, as well as reduced heart non-protein antioxidant levels (P < 0.05). TTR animals exhibited higher levels of parasitemia, myocarditis, hydrogen peroxide, malondialdehyde, IFN-γ, TNF-α and IL-6 than STR animals (P < 0.05), which showed the lowest levels of all analyzed parameters compared to the other groups (P < 0.05). Our findings indicate that exercise aggravates acute infection. When concomitantly administered with benznidazole, exercise training impaired parasitic control and chemotherapy-induced cardioprotection in T. cruzi-infected rats. Considering that exercise training and T. cruzi infection constitute independent metabolic challenges, the negative effects of concomitant treatment are potentially related to the overlapping oxidative and immunoinflammatory demands of exercise and the infection itself.


Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/metabolismo , Catalase/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Cardiomiopatia Chagásica/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Coração/fisiologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Masculino , Miocardite/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Nitroimidazóis/farmacologia , Parasitemia/parasitologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo
8.
Acta Trop ; 195: 51-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31022383

RESUMO

Trypanosoma cruzi, responsible for Chagas disease, is a serious public health problem in Latin America with eight million people infected in the world. Clinical manifestations observed in humans due to T. cruzi infection are largely associated with the wide biological and genetic heterogeneity of the parasite. This review presents an overview of the parasitological aspects of various strains of T. cruzi isolated mainly in Mexico, as well as an analysis of the methodological processes used to determine their virulence that could be influencing their biological characterization. We emphasize the importance of using uniform protocols to study T. cruzi virulence, taking into account factors related to: strain (i.e. developmental stage, lineage, biological origin, genetic variability), animal model used (i.e. role of hormones, host immune response, age) and methodology (i.e. inoculum size, inoculation route, and laboratory conditions used during strain maintenance). These uniform protocols will then allow proposing elements for understanding clinical evolution and management of the disease, for providing adequate treatment, and for developing tools for future vaccines against Chagas disease.


Assuntos
Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/terapia , Modelos Animais de Doenças , Humanos , México , Virulência
9.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022871

RESUMO

Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against a wide panel of bacteria, fungi and parasitic protozoa. Forty-five compounds were identified in the studied EO, of which lavandulyl acetate (40.1%) and thymyl isobutyrate (13.9%) were the major components. The EO did not inhibit bacterial or fungal growth at the maximum concentration tested (64 µg/mL), although it displayed activity on all evaluated protozoa (IC50 values ranging from 2.2 to 56.6 µg/mL). In parallel, the EO demonstrated a noteworthy cytotoxic activity against peritoneal macrophages (CC50 values of 28.0 µg/mL). The most sensitive microorganism was Trypanosoma cruzi, which had a superior activity (IC50 = 2.2 µg/mL) and selectivity (SI = 13) in respect to other parasitic protozoa and the reference drug (p < 0.05). Further in vivo studies are needed to evaluate the potential use of this EO and the main compounds as antitrypanosomal agents. To our knowledge, this is the first report of chemical characterization and antimicrobial assessment of the EO from P. matricarioides.


Assuntos
Asteraceae/química , Proliferação de Células/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Óleos Voláteis/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antiparasitários/química , Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Fungos/efeitos dos fármacos , Fungos/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade
10.
PLoS One ; 14(4): e0214193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939131

RESUMO

Cocos nucifera (C. nucifera) (the coconut palm tree) has been traditionally used to fight a number of human diseases, but only a few studies have tested its components against parasites such as those that cause malaria. In this study, C. nucifera samples were collected from a private natural reserve in Punta Patiño, Darien, Panama. The husk, leaves, pulp, and milk of C. nucifera were extracted and evaluated against the parasites that cause Chagas' disease or American trypanosomiasis (Trypanosoma cruzi), leishmaniasis (Leishmania donovani) and malaria (Plasmodium falciparum), as well as against a line of breast cancer cells. While there was no activity in the rest of the tests, five and fifteen-minute aqueous decoctions of leaves showed antiplasmodial activity at 10% v/v concentration. Removal of some HPLC fractions resulted in loss of activity, pointing to the presence of synergy between the components of the decoction. Chemical molecules were separated and identified using an ultra-performance liquid chromatography (UPLC) approach coupled to tandem mass spectrometry (LC-MS/MS) using atmospheric pressure chemical ionization quadrupole-time of flight mass spectrometry (APCI-Q-TOF-MS) and molecular networking analysis, revealing the presence of compounds including polyphenol, flavone, sterol, fatty acid and chlorophyll families, among others.


Assuntos
Antiparasitários/farmacologia , Cocos/química , Leishmaniose/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antiparasitários/química , Arecaceae/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Leishmaniose/parasitologia , Malária Falciparum/parasitologia , Panamá , Folhas de Planta/química , Espectrometria de Massas em Tandem , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade
11.
Parasitol Res ; 118(5): 1493-1500, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30847614

RESUMO

Oral infection by Trypanosoma cruzi has been responsible for frequent outbreaks of acute Chagas disease in the north of South America and in the Amazon region, where T. cruzi genetic group TcI predominates. TcI strains from different geographical regions have been used in oral infection in mice, but there is no information about strains from Mexico where TcI is prevalent. Here, we analyzed four Mexican strains as concerns the course of oral infection, the ability to invade host cells in vitro, and the profile of metacyclic trypomastigote surface molecules gp82 and gp90 that are implicated in parasite internalization. Oral infection of mice with metacyclic forms of all strains resulted in reduced blood and tissue parasitism, and mild to moderate inflammatory process in the heart/skeletal muscle. They expressed pepsin-resistant gp82 and gp90 molecules at high levels and invaded host cells poorly in full nutrient medium and efficiently under nutrient-deprived condition. The properties exhibited by Mexican strains were similar to those displayed by TcI strains from other geographical regions, reinforcing the notion that these features are common to the genetic group TcI as a whole.


Assuntos
Doença de Chagas/transmissão , Proteínas de Protozoários/biossíntese , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Glicoproteínas Variantes de Superfície de Trypanosoma/biossíntese , Animais , Linhagem Celular Tumoral , Doença de Chagas/parasitologia , Células HeLa , Humanos , México , Camundongos , Proteínas de Protozoários/genética , América do Sul , Trypanosoma cruzi/classificação , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
12.
Parasitol Res ; 118(4): 1325-1329, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747295

RESUMO

Chagas disease is caused by Trypanosoma cruzi and remains one of the most neglected diseases in Latin America. One of its clinical forms is Chagas megacolon. Despite being known for more than half a century, detailed causes are still obscure. Recent evidence indicates a close relationship between the immune system and the enteric nervous system in the etiology of chagasic megacolon pathology. It is believed that low expression of the 5-HT3A serotonin receptor on lymphocytes could be linked to megacolon development. To test this hypothesis, this work investigated the distribution of CD4, CD8, and CD20 lymphocytes and their 5-HT3A receptor expression. The results demonstrated that Chagas patients without megacolon present a higher expression of the 5-HT3A receptor in all analyzed lymphocytes compared with Chagas patients with megacolon. These data suggest that the high expression of this receptor may lead to immunomodulation and prevent the development of Chagas megacolon.


Assuntos
Doença de Chagas/patologia , Sistema Nervoso Entérico/patologia , Sistema Imunitário/patologia , Megacolo/patologia , Receptores 5-HT3 de Serotonina/metabolismo , Antígenos CD20/análise , Antígenos CD4/análise , Antígenos CD8/análise , Humanos , Linfócitos/metabolismo , Linfócitos/parasitologia , Megacolo/parasitologia , Pessoa de Meia-Idade , Serotonina , Trypanosoma cruzi/patogenicidade
13.
Am J Trop Med Hyg ; 100(2): 296-302, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30734691

RESUMO

Chagas disease is one of the most significant systemic parasitosis in Latin America, caused by Trypanosoma cruzi, which is mainly transmitted by hematophagous insects, the triatomines. This research was carried out in both domestic and wild environments throughout a Northeastern rural locality. Triatomines were captured in both peridomicile and wild environments, obtaining 508 specimens of triatomines, of which 99.6% were Triatoma brasiliensis. Insects were captured in 10 (18.5%) peridomiciles with an average of 8.3 triatomines per residence. Triatoma brasiliensis nymphs and adults were found in six peridomiciles, generating a 11.1% colonization. No T. cruzi infection was detected in the 447 peridomestic insects analyzed. On the other hand, of the 55 sylvatic T. brasiliensis molecularly examined for T. cruzi, 12 (21%) were positive, all harboring T. cruzi I. The blood meal analysis by enzyme-linked immunosorbent assay from gut content revealed that both peridomestic and wild triatomine populations fed mainly on birds, refractory to the parasite, which may explain the null rate of natural infection prevalence in the domestic environment. However, infected triatomines for potential home infestation within the radius of insect dispersion capacity were registered in rock outcrops around the dwellings. Anthropogenic environmental influences are able to rapidly alter these scenarios. Therefore, to avoid disease transmission to humans, we recommend constant vector control combined with periodic serological surveillance. The associated methodology presented herein may serve as a model for early detections of risk factors for Chagas disease transmission in the Brazilian Northeast.


Assuntos
Doença de Chagas/epidemiologia , Doença de Chagas/transmissão , Insetos Vetores/parasitologia , Ninfa/parasitologia , Triatoma/parasitologia , Adolescente , Adulto , Idoso , Animais , Animais Domésticos/parasitologia , Animais Selvagens/parasitologia , Aves/parasitologia , Brasil/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/prevenção & controle , Criança , Pré-Escolar , Características da Família , Feminino , Humanos , Lactente , Recém-Nascido , Controle de Insetos/organização & administração , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População Rural , Trypanosoma cruzi/patogenicidade , Trypanosoma cruzi/fisiologia
14.
Phytomedicine ; 56: 27-34, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668348

RESUMO

BACKGROUND: Deoxymikanolide is a sesquiterpene lactone isolated from Mikania micrantha and M. variifolia which, has previously demonstrated in vitro activity on Trypanosoma cruzi and in vivo activity on an infected mouse model. PURPOSE: Based on these promising findings, the aim of this study was to investigate the mechanism of action of this compound on different parasite targets. METHODS: The interaction of deoxymikanolide with hemin was examined under reducing and non- reducing conditions by measuring modifications in the Soret absorption band of hemin; the thiol interaction was determined spectrophotometrically through its reaction with 5,5'-dithiobis-2-nitrobenzoate in the presence of glutathione; activity on the parasite antioxidant system was evaluated by measuring the activity of the superoxide dismutase and trypanothione reductase enzymes, together with the intracellular oxidative state by flow cytometry. Superoxide dismutase and trypanothione reductase activities were spectrophotometrically tested. Cell viability, phosphatidylserine exposure and mitochondrial membrane potential were assessed by means of propidium iodide, annexin-V and rhodamine 123 staining, respectively; sterols were qualitatively and quantitatively tested by TLC; ultrastructural changes were analyzed by transmission electron microscopy. Autophagic cells were detected by staining with monodansylcadaverine. RESULTS: Deoxymikanolide decreased the number of reduced thiol groups within the parasites, which led to their subsequent vulnerability to oxidative stress. Treatment of the parasites with the compound produced a depolarization of the mitochondrial membrane even though the plasma membrane permeabilization was not affected. Deoxymikanolide did not affect the intracellular redox state and so the mitochondrial dysfunction produced by this compound could not be attributed to ROS generation. The antioxidant defense system was affected by deoxymikanolide at twenty four hours of treatment, when both an increased oxidative stress and decreased activity of superoxide dismutase and trypanothione reductase (40 and 60% respectively) were observed. Both the oxidative stress and mitochondrial dysfunction induce parasite death by apoptosis and autophagy. CONCLUSION: Based on our results, deoxymikanolide would exert its anti-T cruzi activity as a strong thiol blocking agent and by producing mitochondrial dysfunction.


Assuntos
Lactonas/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Glutationa/metabolismo , Hemina/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mikania/química , NADH NADPH Oxirredutases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Esteróis/biossíntese , Superóxido Dismutase/metabolismo , Trypanosoma cruzi/patogenicidade , Trypanosoma cruzi/ultraestrutura
15.
PLoS Negl Trop Dis ; 13(1): e0007044, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689662

RESUMO

The population genetics of Triatoma dimidiata haplogroups was analyzed at landscape and sub-regional scales in Chiapas and regional level across the Mexican Neotropics, and phylogeography of the complex was re-analyzed across its complete geographic range. Two contiguous fragments of the ND4 gene were analyzed due to bias from differential haplogroup specificity using a previously designed sequence. At both landscape (anthropic modification gradient) and regional (demographic, fragmentation, biogeographic, climate) scales, lowest T. dimidiata genetic diversity occurs where there is greatest historical anthropic modification, and where T. cruzi infection prevalence is significantly highest. Trypanosoma cruzi prevalence was significantly higher than expected in haplogroups 1 and 3, while lower than expected in haplogroup 2. There was also a significant difference of DTUI and DTUVI infection frequencies in both haplogroups 1 and 3, while no difference of either in haplogroup 2. All haplogroups from the Mexican Neotropics had moderate to high haplotype diversity, while greatest genetic differentiation was between haplogroups 1 and 3 (above FST = 0.868, p < 0.0001). Divergence of the complex from the MRCA was estimated between 0.97 MYA (95% HPD interval = 0.55-1.53 MYA) and 0.85 MYA (95% HPD interval = 0.42-1.5 MYA) for ND4A and both concatenated fragments, respectively, with primary divergence from the MRCA of haplogroups 2 and 3. Effective population size for Mexican haplogroups 1 and 2 increased between 0.02 and 0.03 MYA. This study supports previous ecological niche evidence for the complex´s origin surrounding the Tehuantepec Isthmus, and provides evidence for recent divergence of three primary dimidiata haplogroups, with differential T. cruzi infection frequency and DTU specificity, important components of vector capacity.


Assuntos
Doença de Chagas/parasitologia , Variação Genética , Triatoma/classificação , Triatoma/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/epidemiologia , Ecossistema , Haplótipos , Humanos , Proteínas de Insetos/genética , México/epidemiologia , NADH Desidrogenase/genética , Filogenia , Filogeografia , Triatoma/genética
16.
Transfusion ; 59(1): 287-294, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30474861

RESUMO

BACKGROUND: Chagas disease is caused by Trypanosoma cruzi and is endemic in Latin America. In nonendemic countries, including Japan, Chagas disease is primarily a problem in the context of transfusion transmission. Approximately 250,000 immigrants from Latin America reside in Japan, and many of those individuals serve as active blood donors. This study surveyed the seroprevalence of T. cruzi infection among at-risk blood donors in Japan, defined as those who themselves (or whose mothers) were born (or raised) in Latin America, or those with a travel history to Latin America. STUDY DESIGN AND METHODS: Blood samples were obtained from at-risk donors in two periods, 2004-2012 and 2013-2016. Collected samples were tested for T. cruzi antibodies using both an enzyme-linked immunosorbent assay and a chemiluminescent immunoassay. Samples that tested positive in both assays were additionally tested by polymerase chain reaction, and look-back investigation was conducted when necessary. RESULTS: Of 18,484 samples obtained from 18,076 at-risk donors, 3 (1:6,025, 0.017%) donors showed seroreactivity by enzyme-linked immunosorbent assay and chemiluminescent immunoassay. All antibody-positive donors were born in Latin America. One of them also was positive for T. cruzi DNA. Eleven previous donations from this donor were subjected to look-back investigation, and five recipients were tested. All five recipients tested negative for T. cruzi antibodies. CONCLUSION: Seroprevalence of T. cruzi was 0.017% among at-risk donors in Japan. Transfusion-transmitted infection of Chagas disease has not been confirmed to date. Screening for T. cruzi antibodies by targeting at-risk donors is an appropriate strategy for ensuring blood safety in Japan.


Assuntos
Doença de Chagas/epidemiologia , Trypanosoma cruzi/patogenicidade , Anticorpos Antiprotozoários/imunologia , Doadores de Sangue/estatística & dados numéricos , Doença de Chagas/imunologia , DNA de Protozoário/genética , Feminino , Humanos , Imunoensaio , Japão , Masculino , Trypanosoma cruzi/genética
17.
Exp Parasitol ; 197: 68-75, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30439347

RESUMO

BACKGROUND: In recent decades some outbreaks of food-borne acute Chagas disease (ACD) in humans were identified by clinical and epidemiological characterization after association through the ingestion of açaí pulp probably contaminated with Trypanosoma cruzi. Whereas Belém and Abaetetuba stood out as important risk regions for disease transmission, the importance of Rhodnius pictipes, and Philander opossum for the biological cycle of T. cruzi, and data from agribusiness market of açaí, to study T. cruzi from vector and reservoir of the Brazilian Amazon region is critical for this context. Thus, the purpose of this study was to verify the infective capacity and the virulence of T. cruzi in açaí pulp from vector and reservoir at Pará State experimentally. METHODS: 105T. cruzi I in in natura açaí pulp from Belém at Pará State, at room temperature, after forced sieving, by intraperitoneal, gavage or oral route of inoculation in B6.129S7Rag1-/-tmMom/J Unib allowed food-borne ACD analysis using common light microscopy. PRINCIPAL FINDINGS: T. cruzi in in natura açaí pulp from R. pictipes (Val-De-Cans Forest, Belém, and Ajuaí River, Abaetetuba, Pará), and P. opossum (Combu Island, Belém, Pará) caused ACD and death between 17 and 52 days after experimental infections in murine immunodeficient hosts. CONCLUSIONS: T. cruzi from different sources and locations at Pará State in in natura açaí pulp retained its infective capacity and virulence, and can cause new outbreaks of ACD by oral transmission. Additionally, quality basic education will facilitate efficient hygiene practices throughout the açaí productive chain can eradicate food-borne ACD in the coming decades.


Assuntos
Doença de Chagas/transmissão , Euterpe/parasitologia , Parasitologia de Alimentos , Doenças Transmitidas por Alimentos/parasitologia , Trypanosoma cruzi/patogenicidade , Doença Aguda , Animais , Brasil/epidemiologia , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Reservatórios de Doenças/parasitologia , Vetores de Doenças , Feminino , Doenças Transmitidas por Alimentos/epidemiologia , Insetos Vetores/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos , Gambás/parasitologia , Parasitemia/epidemiologia , Parasitemia/mortalidade , Rhodnius/parasitologia , Virulência
18.
Free Radic Biol Med ; 130: 408-418, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445126

RESUMO

Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from ß-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required.


Assuntos
Doença de Chagas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/genética , Doença de Chagas/parasitologia , Humanos , Peróxido de Hidrogênio , Imidazóis/química , Imidazóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Naftoquinonas/química , Compostos Organofosforados/farmacologia , Piperidinas/farmacologia , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/patogenicidade
19.
J Leukoc Biol ; 105(1): 163-175, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30371945

RESUMO

IL-10 is a pleiotropic cytokine with immunoregulatory functions affecting various cell types. In a model of experimental infection with the protozoan Trypanosoma cruzi (T. cruzi), we found increased morbidity and lower parasite control in IL-10 deficient mice (IL-10 KO) compared to wild-type (WT) mice. Despite enhanced Mϕ function and dendritic cell activation, IL-10 KO mice were more susceptible to infection. The kinetics of T cells in spleen and peripheral blood revealed that infected IL-10 KO mice failed to increase the number of spleen and circulating total CD8+ T cells, a phenomenon observed from the second week of infection in WT mice. Total CD8+ T cells from IL-10 KO mice exhibited diminished proliferation, cytotoxic potential and IFN-γ production than their WT counterparts and T. cruzi-specific CD8+ T cells displayed reduced in vivo cytotoxicity. The absence of IL-10 selectively affected expansion, survival, and increased PD-1 expression of CD8+ T cells without altering these same parameters on CD4+ T cells. Increased inhibitory receptors expression and down-modulation of T-bet by CD8+ T cells from IL-10 KO infected mice were compatible with a T cell exhaustion phenotype. Collectively, these findings reveal that during acute infection, IL-10 plays a previously unrecognized stimulatory role on CD8+ T cells, the most relevant lymphocyte population for the control of intracellular T. cruzi stages. A clear knowledge of the underlying mechanisms that drive effector functions of cytotoxic T cells is critical to understand pathogen persistence and rational design of prophylactic strategies against T. cruzi.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Interleucina-10/metabolismo , Ativação Linfocitária/imunologia , Trypanosoma cruzi/patogenicidade , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Interleucina-2/biossíntese , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interleucina-10/metabolismo , Proteínas Recombinantes/farmacologia , Baço/patologia , Virulência
20.
Curr Med Chem ; 26(36): 6519-6543, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30381063

RESUMO

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host's immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Doença de Chagas/fisiopatologia , Trypanosoma cruzi/patogenicidade , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença Crônica/tratamento farmacológico , Progressão da Doença , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Nitroimidazóis/uso terapêutico , Fatores de Risco , Trypanosoma cruzi/efeitos dos fármacos
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