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1.
Exp Parasitol ; 218: 108012, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33011239

RESUMO

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in almost all countries of Latin America. In Brazil, oral infection is becoming the most important mechanism of transmission of the disease in several regions of the country. The gastrointestinal tract is the gateway for the parasite through this route of infection, however, little is known about the involvement of these organs related to oral route. In this sense, the present study evaluated the impact of oral infection on the digestive tract in mice infected by Berenice-78 (Be-78) T. cruzi strain, in comparison with the intraperitoneal route of infection. In this work, the intraperitoneal route group showed a peak of parasitemia similar to the oral route group, however the mortality rate among the orally infected animals was higher when compared to intraperitoneal route. By analyzing the frequency of blood cell populations, differences were mainly observed in CD4+ T lymphocytes, and not in CD8+, presenting an earlier reduction in the number of CD4+ T cells, which persisted for a longer period, in the animals of the oral group when compared with the intraperitoneal group. Animals infected by oral route presented a higher tissue parasitism and inflammatory infiltrate in stomach, duodenum and colon on the 28th day after infection. Therefore, these data suggest that oral infection has a different profile of parasitological and immune responses compared to intraperitoneal route, being the oral route more virulent and with greater tissue parasitism in organs of the gastrointestinal tract evaluated during the acute phase.


Assuntos
Doença de Chagas/patologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/parasitologia , Trypanosoma cruzi/patogenicidade , Administração Oral , Análise de Variância , Animais , Doença de Chagas/mortalidade , Doença de Chagas/parasitologia , Colo/parasitologia , Colo/patologia , Duodeno/parasitologia , Duodeno/patologia , Imunofenotipagem , Masculino , Camundongos , Monócitos/patologia , Parasitemia/mortalidade , Parasitemia/parasitologia , Estômago/parasitologia , Estômago/patologia , Taxa de Sobrevida
2.
PLoS Negl Trop Dis ; 14(9): e0008712, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970687

RESUMO

BACKGROUND: Several studies addressed changes on the insect vector behavior due to parasite infection, but little is known for triatomine bugs, vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. We assessed infection rates and metacyclogenesis of T. cruzi (TcVI) in fifth-instar nymphs of Triatoma rubrovaria comparing with the primary vector Triatoma infestans. Also, biological parameters related to feeding-excretion behavior were evaluated aiming to identify which variables are most influenced by T. cruzi infection. METHODOLOGY/PRINCIPAL FINDINGS: Fifth-instar nymphs of T. rubrovaria and T. infestans were fed on mice infected with T. cruzi (TcVI). We compared the presence and the number of parasite evolutive forms in excreta of both triatomine species at 30, 60 and 90 days post-infection (dpi) with traditional statistical analyses. Moreover, both species were analyzed through generalized linear models and multinomial logistic regression hypotheses for seven behavioral parameters related to host-seeking and feeding-excretion. Triatoma rubrovaria and T. infestans had similar overall infection and metacyclogenesis rates of T. cruzi TcVI in laboratory conditions. Regarding vector behavior, we confirmed that the triatomine's tendency is to move away from the bite region after a blood meal, probably to avoid being noticed by the vertebrate host. Interspecific differences were observed on the volume of blood ingested and on the proportion of individuals that excreted after the blood meal, revealing the higher feeding efficiency and dejection rates of T. infestans. The amount of ingested blood and the bite behavior of T. rubrovaria seems to be influenced by TcVI infection. Infected specimens tended to ingest ~25% more blood and to bite more the head of the host. Noteworthy, in two occasions, kleptohematophagy and coprophagy behaviors were also observed in T. rubrovaria. CONCLUSIONS/SIGNIFICANCE: Laboratory infections revealed similar rate of T. cruzi TcVI trypomatigotes in excreta of T. rubrovaria and T. infestans, one of the most epidemiological important vectors of T. cruzi. Therefore, TcVI DTU was able to complete its life cycle in T. rubrovaria under laboratory conditions, and this infection changed the feeding behavior of T. rubrovaria. Considering these results, T. rubrovaria must be kept under constant entomological surveillance in Rio Grande do Sul, Brazil.


Assuntos
Comportamento Alimentar , Insetos Vetores/fisiologia , Insetos Vetores/parasitologia , Triatoma/fisiologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Brasil , Doença de Chagas/transmissão , Modelos Animais de Doenças , Interações Hospedeiro-Parasita , Mordeduras e Picadas de Insetos , Modelos Logísticos , Camundongos , Ninfa , Eliminação Renal , Trypanosoma cruzi/patogenicidade
3.
PLoS Pathog ; 16(8): e1008781, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810179

RESUMO

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays.


Assuntos
Doença de Chagas/metabolismo , Fibroblastos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Ativação de Neutrófilo , Neutrófilos , Trypanosoma cruzi/metabolismo , Doença de Chagas/genética , Doença de Chagas/patologia , Fibroblastos/metabolismo , Fibroblastos/parasitologia , Fibroblastos/patologia , Humanos , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Neutrófilos/patologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
4.
Am J Trop Med Hyg ; 103(3): 967-969, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32602437

RESUMO

In the United States, Chagas disease is diagnosed in less than 1% of the estimated > 300,000 people who have the disease. However, the actual prevalence remains unknown, and these estimates may be wide of the mark (too high or too low). The greater part of those living with the disease acquired the infection in an endemic region of Latin America, but autochthonous transmission in the United States is increasingly being described. These cases are considered rare, and the transmission routes are largely unknown. Although triatomines or "kissing bugs" harbor Trypanosoma cruzi in North America, most autochthonous cases are presumed rather than confirmed exposures to naturally infected kissing bugs. Public knowledge of Chagas is growing, and efforts are underway to provide greater awareness, but what are the risk factors for human transmission of Chagas disease in the United States?


Assuntos
Doença de Chagas/epidemiologia , Doença de Chagas/transmissão , Insetos Vetores/parasitologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/parasitologia , Transmissão de Doença Infecciosa , Humanos , América Latina/epidemiologia , Prevalência , Trypanosoma cruzi/patogenicidade , Incerteza , Estados Unidos/epidemiologia
5.
PLoS Pathog ; 16(4): e1008474, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315358

RESUMO

Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas cardiomyopathy. In the present study, we investigated the role of extracellular vesicles (Ev) in shaping the macrophage (Mφ) response in progressive Chagas disease (CD). We purified T. cruzi Ev (TcEv) from axenic parasite cultures, and T. cruzi-induced Ev (TEv) from the supernatants of infected cells and plasma of acutely and chronically infected wild-type and Parp1-/- mice. Cultured (Raw 264.7) and bone-marrow Mφ responded to TcEV and TEv with a profound increase in the expression and release of TNF-α, IL-6, and IL-1ß cytokines. TEv produced by both immune (Mφ) and non-immune (muscle) cells were proinflammatory. Chemical inhibition or genetic deletion of PARP1 (a DNA repair enzyme) significantly depressed the TEv-induced transcriptional and translational activation of proinflammatory Mφ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory Mφ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NFκB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NFκB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-α+ Mφ in the myocardium of CD wild-type mice. In comparison, chronically infected Parp1-/- mice exhibited low-to-moderate tissue inflammation, >80% decline in myocardial infiltration of TNF-α+ Mφ, and no change in immunoregulatory IL-10+ Mφ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-κB pathway of proinflammatory Mφ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the Mφ activation and controlling the chronic inflammation in CD.


Assuntos
Doença de Chagas/metabolismo , Vesículas Extracelulares/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , Nucleotidiltransferases/imunologia , Poli(ADP-Ribose) Polimerase-1/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/imunologia , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
6.
Biochim Biophys Acta Mol Cell Res ; 1867(7): 118694, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32151656

RESUMO

Dot1 enzymes are histone methyltransferases that mono-, di- and trimethylate lysine 79 of histone H3 to affect several nuclear processes. The functions of these different methylation states are still largely unknown. Trypanosomes, which are flagellated protozoa that cause several parasitic diseases, have two Dot1 homologues. Dot1A catalyzes the mono- and dimethylation of lysine 76 during late G2 and mitosis, and Dot1B catalyzes trimethylation, which is a modification found in all stages of the cell cycle. Here, we generated Trypanosoma cruzi lines lacking Dot1B. Deletion of one allele resulted in parasites with increased levels of mono- and dimethylation and a reduction in H3K76me3. In the full knockout (DKO), no trimethylation was observed. Both the DKO and the single knockout (SKO) showed aberrant morphology and decreased growth due to cell cycle arrest after G2. This phenotype could be rescued by caffeine in the DKO, as caffeine is a checkpoint inhibitor of the cell cycle. The knockouts also phosphorylated γH2A without producing extensive DNA breaks, and Dot1B-depleted cells were more susceptible to general checkpoint kinase inhibitors, suggesting that a lack of H3K76 trimethylation prevents the initiation and/or completion of cytokinesis.


Assuntos
Doença de Chagas/genética , Histona-Lisina N-Metiltransferase/genética , Mitose/genética , Trypanosoma cruzi/genética , Ciclo Celular/genética , Doença de Chagas/parasitologia , Histonas/genética , Lisina/genética , Metilação/efeitos dos fármacos , Proteínas Nucleares/genética , Fosforilação/genética , Trypanosoma cruzi/patogenicidade
7.
BMC Infect Dis ; 20(1): 143, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059706

RESUMO

BACKGROUND: Chagas disease is caused by the haemoflagellate protozoan Trypanosoma cruzi. Currently, T. cruzi recognizes seven discrete typing units (DTUs): TcI to TcVI and Tcbat. The genetic diversity of T. cruzi is suspected to influence the clinical outcome. Acute clinical manifestations, which include myocarditis and meningoencephalitis, are sometimes fatal; occur most frequently in children and in immunocompromised individuals. Acute disease is often overlooked, leading to a poor prognosis. CASE PRESENTATION: A 38-year-old man from a subtropical area of the Andes mountains of Ecuador was hospitalized after 3 weeks of evolution with high fever, chills, an enlarged liver, spleen, and lymph nodes, as well as facial edema. ECG changes were also observed. T. cruzi was identified in blood smears, culture and amplification of DNA by PCR. Tests for anti-T. cruzi IgG and IgM and HIV were negative. Molecular typing by restriction fragment length polymorphism (PCR-RFLP) determined the parasite to DTU TcI. In the absence of a timely anti-T. cruzi medication, the patient died. CONCLUSIONS: This is a case of severe pathogenicity and the virulence of a DTU TcI strain in an adult patient. The severe acute Chagas disease was probably overlooked due to limited awareness and its low incidence. Our findings suggest that T. cruzi DTU TcI strains circulating in Ecuador are capable of causing fatal acute disease. Early diagnosis and prompt treatment is of paramount importance to avoid fatalities in acute infections.


Assuntos
Doença de Chagas/etiologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Adulto , Doença de Chagas/parasitologia , Equador , Variação Genética , Humanos , Masculino , Tipagem Molecular , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Trypanosoma cruzi/classificação
8.
Sci Rep ; 10(1): 1853, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024939

RESUMO

Studies of host-parasite relationships largely benefit from adopting a multifactorial approach, including the complexity of multi-host systems and habitat features in their analyses. Some host species concentrate most infection and contribute disproportionately to parasite and vector population maintenance, and habitat feature variation creates important heterogeneity in host composition, influencing infection risk and the fate of disease dynamics. Here, we examine how the availability of specific groups of hosts and habitat features relate to vector abundance and infection risk in 18 vector populations along the Mediterranean-type ecosystem of South America, where the kissing bug Mepraia spinolai is the main wild vector of the parasite Trypanosoma cruzi, the etiological agent of Chagas disease. For each population, data on vectors, vertebrate host availability, vegetation, precipitation, and temperature were collected and analyzed. Vector abundance was positively related to temperature, total vegetation, and European rabbit availability. Infection risk was positively related to temperature, bromeliad cover, and reptile availability; and negatively to the total domestic mammal availability. The invasive rabbit is suggested as a key species involved in the vector population maintenance. Interestingly, lizard species -a group completely neglected as a potential reservoir-, temperature, and bromeliads were relevant factors accounting for infection risk variation across populations.


Assuntos
Doença de Chagas/etiologia , Doença de Chagas/parasitologia , Lagartos/parasitologia , Animais , Ecossistema , Interações Hospedeiro-Parasita/fisiologia , Insetos Vetores/parasitologia , Mamíferos/parasitologia , Coelhos , Risco , América do Sul , Temperatura , Triatominae/parasitologia , Trypanosoma cruzi/patogenicidade
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165689, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001300

RESUMO

This review is a perspective on the history of Chagas disease, and it adopts a novel approach from literary studies, historical documents and the science and epidemiology of the nature of the disease. From this analysis, comes the review's working definition of the Contact Zone (CZ): "the space in which geographically and historically separated people come into contact with each other and establish long-lasting relationships, which usually involve coercive conditions, radical inequality and intolerable conflict." In the Patient-Physician CZ, we verified the triple transition phenomena: the American trypanosomiasis shifted from a rural, acute, and vectorial transmitted disease to an urban, chronic and non-vectorial disease. In the Academic CZ, we describe the original disagreements which denied the existence of the disease and the current controversies about pathogenic mechanisms and etiological treatment. From the News from Latin America, and in the Original CZ, we will review the evolution of different forms of transmission. As in any good story, research across broad disciplines is necessary to reveal historical perspectives, scientific approaches, and the epidemiology of the disease, which has a prequel of 9000 years and an open ending: thus, we explore across the Global CZ, with its multiple and unexpected actors.


Assuntos
Doença de Chagas/história , Erradicação de Doenças/organização & administração , Doenças Endêmicas/história , Doenças Negligenciadas/história , Trypanosoma cruzi/patogenicidade , Animais , Restos Mortais/parasitologia , Doença de Chagas/epidemiologia , Doença de Chagas/prevenção & controle , Doença de Chagas/transmissão , DNA de Protozoário/isolamento & purificação , Erradicação de Doenças/história , Erradicação de Doenças/tendências , Vetores de Doenças , Doenças Endêmicas/prevenção & controle , Antropologia Forense/história , Carga Global da Doença , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/parasitologia , Doenças Negligenciadas/prevenção & controle , Triatoma/parasitologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/isolamento & purificação
10.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165691, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006572

RESUMO

More than 110 years has passed since the first publications on Chagas disease, and it still urges the necessity of understanding it as a complex socioenvironmental issue in which components of diverse nature converge and interact beyond the biomedical and epidemiological aspects. The current scenarios of the issue, both rural and Latin American as urban and global, demand that the education on Chagas disease include all possible contexts: where there are insect vectors and where there are not; inside and outside Latin America; in rural, periurban, and urban areas; in formal and non-formal educational environments. We consider essential the requirement of both an integral approach that overcomes the biomedical aspect to include the multidimensionality of the issue and a dialogical educational perspective that allows individuals and communities to analyze, decide, and lead contextualized prevention and promotion actions regarding their health. In this study, we surveyed, described, and critically analyzed studies approaching the link education-Chagas disease in scientific publications from the last 15 years. We aimed at contributing methodological-theoretical elements to (re)think the development of educational research and experiences that truly help facing this issue. From the electronic search of scientific literature in 6 databases, we found 426 articles, out of which we selected 25. We incorporated 10 articles from other sources to this initial corpus and performed both qualitative and quantitative analyses over the total number [35] to characterize the studied works in general, focusing on the conceptions on the Chagas disease issue and the underlying health education approaches.


Assuntos
Doença de Chagas/prevenção & controle , Doenças Negligenciadas/prevenção & controle , Educação de Pacientes como Assunto , Triatoma/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Pesquisa Biomédica/estatística & dados numéricos , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Controle de Doenças Transmissíveis/economia , Controle de Doenças Transmissíveis/organização & administração , Erradicação de Doenças/economia , Erradicação de Doenças/organização & administração , Vetores de Doenças , Carga Global da Doença , Humanos , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/parasitologia , Política , Publicações/estatística & dados numéricos , Trypanosoma cruzi/genética , Trypanosoma cruzi/isolamento & purificação
11.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165692, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972227

RESUMO

Many important pathogen-host interactions rely on highly specific carbohydrate binding events. In the case of the protozoan Trypanosoma cruzi, the causative agent of Chagas disease, glycointeractions involving sialic acid (SA) residues are pivotal for parasite infectivity, escape from immune surveillance and pathogenesis. Though unable to synthesize SA de novo, T. cruzi displays a unique trans-Sialidase (TS) enzyme, which is able to cleave terminal SA residues from host donor glycoconjugates and transfer them onto parasite surface mucins, thus generating protective/adhesive structures. In addition, this parasite sheds TS into the bloodstream, as a way of modifying the surface SA signature, and thereby the signaling/functional properties of mammalian host target cells on its own advantage. Here, we discuss the pathogenic aspects of T. cruzi TS: its molecular adaptations, the multiplicity of interactions in which it is involved during infections, and the array of novel and appealing targets for intervention in Chagas disease provided by TS-remodeled sialoglycophenotypes.


Assuntos
Doença de Chagas/imunologia , Glicoproteínas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Neuraminidase/metabolismo , Polissacarídeos/imunologia , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Glicoproteínas/imunologia , Humanos , Evasão da Resposta Imune , Neuraminidase/imunologia , Polissacarídeos/química , Polissacarídeos/metabolismo , Proteínas de Protozoários/imunologia , Ácidos Siálicos/química , Ácidos Siálicos/imunologia , Ácidos Siálicos/metabolismo , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/imunologia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo
12.
Dis Markers ; 2019: 3632906, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885735

RESUMO

A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-ß are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-ß and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Galectinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Remodelamento Atrial , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Transdução de Sinais , Trypanosoma cruzi/patogenicidade , Remodelação Ventricular
13.
Mediators Inflamm ; 2019: 5091630, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772504

RESUMO

Infection with the protozoan Trypanosoma cruzi causes Chagas disease and consequently leads to severe inflammatory heart condition; however, the mechanisms driving this inflammatory response have not been completely elucidated. Nitric oxide (NO) is a key mediator of parasite killing in T. cruzi-infected mice, and previous studies have suggested that leukotrienes (LTs) essentially regulate the NO activity in the heart. We used infected 5-lipoxygenase-deficient mice (5-LO-/-) to explore the participation of nitric oxide synthase isoforms, inducible (iNOS) and constitutive (cNOS), in heart injury, cytokine profile, and oxidative stress during the early stage of T. cruzi infection. Our evidence suggests that the cNOS of the host is involved in the resistance of 5-LO-/- mice during T. cruzi infection. iNOS inhibition generated a remarkable increase in T. cruzi infection in the blood and heart of mice, whereas cNOS inhibition reduced cardiac parasitism (amastigote nests). Furthermore, this inhibition associates with a higher IFN-γ production and lower lipid peroxidation status. These data provide a better understanding about the influence of NO-interfering therapies for the inflammatory response toward T. cruzi infection.


Assuntos
Araquidonato 5-Lipoxigenase/sangue , Doença de Chagas/sangue , Doença de Chagas/enzimologia , Animais , Antioxidantes/metabolismo , Citocinas/sangue , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/sangue , Trypanosoma cruzi/patogenicidade
14.
PLoS One ; 14(11): e0225386, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31756194

RESUMO

Chagas disease is caused by the protozoan Trypanosoma cruzi, affecting around 8 million people worldwide. After host cell invasion, the infective trypomastigote form remains 2-4 hours inside acidic phagolysosomes to differentiate into replicative amastigote form. In vitro acidic-pH-induced axenic amastigogenesis was used here to study this step of the parasite life cycle. After three hours of trypomastigote incubation in amastigogenesis promoting acidic medium (pH 5.0) or control physiological pH (7.4) medium samples were subjected to three rounds of centrifugation followed by ultrafiltration of the supernatants. The resulting exoproteome samples were trypsin digested and analysed by nano flow liquid chromatography coupled to tandem mass spectrometry. Computational protein identification searches yielded 271 and 483 protein groups in the exoproteome at pH 7.4 and pH 5.0, respectively, with 180 common proteins between both conditions. The total amount and diversity of proteins released by parasites almost doubled upon acidic incubation compared to control. Overall, 76.5% of proteins were predicted to be secreted by classical or non-classical pathways and 35.1% of these proteins have predicted transmembrane domains. Classical secretory pathway analysis showed an increased number of mucins and mucin-associated surface proteins after acidic incubation. However, the number of released trans-sialidases and surface GP63 peptidases was higher at pH 7.4. Trans-sialidases and mucins are anchored to the membrane and exhibit an enzyme-substrate relationship. In general, mucins are glycoproteins with immunomodulatory functions in Chagas disease, present mainly in the epimastigote and trypomastigote surfaces and could be enzymatically cleaved and released in the phagolysosome during amastigogenesis. Moreover, evidence for flagella discard during amastigogenesis are addressed. This study provides the first comparative analysis of the exoproteome during amastigogenesis, and the presented data evidence the dynamism of its profile in response to acidic pH-induced differentiation.


Assuntos
Doença de Chagas/parasitologia , Proteômica/métodos , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/patogenicidade , Doença de Chagas/metabolismo , Cromatografia Líquida , Células HeLa , Interações Hospedeiro-Parasita , Humanos , Concentração de Íons de Hidrogênio , Estágios do Ciclo de Vida , Espectrometria de Massas em Tandem , Trypanosoma cruzi/metabolismo
15.
Mediators Inflamm ; 2019: 7214798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31636507

RESUMO

Dendritic cells (DCs) are a type of antigen-presenting cells that play an important role in the immune response against Trypanosoma cruzi, the causative agent of Chagas disease. In vitro and in vivo studies have shown that the modulation of these cells by this parasite can directly affect the innate and acquired immune response of the host in order to facilitate its biological cycle and the spreading of the species. Many studies show the mechanisms by which T. cruzi modulates DCs, but the interaction of these cells with the Mexican strains of T. cruzi such as Ninoa and INC5 has not yet been properly investigated. Here, we evaluated whether Ninoa and INC5 strains evaded the immunity of their hosts by modulating the biology and function of murine DCs. The CL-Brener strain was used as the reference strain. Herein, it was demonstrated that Ninoa was more infective toward bone marrow-derived dendritic cells (BMDCs) than INC5 and CL-Brener strains in both BMDCs of BALB/c and C57BL/6 mice. Mexican strains of T. cruzi induced different cytokine patterns. In BMDCs obtained from BALB/c mice, Ninoa strain led to the reduction in IL-6 and increased IL-10 production, while in C57BL/6 mice Ninoa strain considerably increased the productions of TNF-α and IL-10. Also, Ninoa and INC5 differentially modulated BMDC expressions of MHC-II, TLR2, and TLR4 in both BALB/c and C57BL/6 mice compared to Brazilian strain CL-Brener. These results indicate that T. cruzi Mexican strains differentially infect and modulate MHC-II, toll-like receptors, and cytokine production in DCs obtained from C57BL/6 and BALB/c mice, suggesting that these strains have developed particular modulatory strategies to disrupt DCs and, consequently, the host immune responses.


Assuntos
Células da Medula Óssea/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Trypanosoma cruzi/patogenicidade , Animais , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
16.
PLoS One ; 14(10): e0223611, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596874

RESUMO

BACKGROUND: The National Army of Colombia is present in all of the national territory, focused in sylvatic zones where they are exposed continually to potential risk of transmission of Trypanosoma cruzi, the etiological agent of the Chagas disease. People of this study were active personal that were born and lived during their first years in endemic areas of transmission through domiciled vectors as Rhodnius prolixus. AIM: The main aim of this study was to estimate the prevalence of Chagas disease in the active military population of the National Army, gathered in five departments. METHODS: An observational and descriptive study with cross-sectional analysis was carried out. Blood sample each patient in order to apply serological diagnosis by two different Enzyme Linked ImmunoSorbent Assay tests, following the algorithm of National Institute of Health, Colombia. In cases of serum results with inconsistencies, a Hemagglutination Inhibition test and Indirect Immunofluorescence assay test were performed to solve inconclusiveness. Positive samples by two different tests were considered seropositive. Additionally, to each positive sample by at least one serological test, we did extraction of DNA for molecular diagnosis. RESULTS: 295 serums were analyzed and two of them were positive in order to get a prevalence of 0.68%. Two samples analyzed by molecular diagnosis were negative. CONCLUSION: The prevalence was < 1% It is probable the infection in the seropositive individuals occurred before enlisting in the military service due to origin locations with transmission such as Casanare and Boyacá. These findings allow defining the prevention and control programs of chronic cases and reduction in the disease burden.


Assuntos
Doença de Chagas/epidemiologia , Militares/estatística & dados numéricos , Adulto , Doença de Chagas/parasitologia , Colômbia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Trypanosoma cruzi/patogenicidade
17.
Infect Genet Evol ; 76: 104041, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31536808

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, is one of the most neglected diseases in Latin America, being currently a global health problem. Its immunopathogenesis is still quite unknown. Moreover, there are important differences in pathogenicity between some different T. cruzi strains. For example, in mice, Y strain produces a high acute lethality while VFRA remains in the host mostly in a chronic manner. Comparative proteomic studies between T. cruzi strains represent a complement for transcriptomics and may allow the detection of relevant factors or distinctive functions. Here for the first time, we compared the proteome of trypomastigotes from 2 strains, Y and VFRA, analyzed by mass spectrometry. Gene ontology analysis were used to display similarities or differences in cellular components, biological processes and molecular functions. Also, we performed metabolic pathways enrichment analysis to detect the most relevant pathways in each strain. Although in general they have similar profiles in the different ontology groups, there were some particular interesting differences. Moreover, there were around 10% of different proteins between Y and VFRA strains, that were shared by other T. cruzi strains or protozoan species. They displayed many common enriched metabolic pathways but some others were uniquely enriched in one strain. Thus, we detected enriched antioxidant defenses in VFRA that could correlate with its ability to induce a chronic infection in mice controlling ROS production, while the Y strain revealed a great enrichment of pathways related with nucleotides and protein production, that could fit with its high parasite replication and lethality. In summary, Y and VFRA strains displayed comparable proteomes with some particular distinctions that could contribute to understand their different biological behaviors.


Assuntos
Proteômica/métodos , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/classificação , Animais , Chlorocebus aethiops , Espectrometria de Massas , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade , Células Vero , Fatores de Virulência/metabolismo
18.
Metabolomics ; 15(9): 117, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31440849

RESUMO

INTRODUCTION: Chagas disease, the most important parasitic infection in Latin America, is caused by the intracellular protozoan Trypanosoma cruzi. To treat this disease, only two nitroheterocyclic compounds with toxic side effects exist and frequent treatment failures are reported. Hence there is an urgent need to develop new drugs. Recently, metabolomics has become an efficient and cost-effective strategy for dissecting drug mode of action, which has been applied to bacteria as well as parasites, such as different Trypanosome species and forms. OBJECTIVES: We assessed if the metabolomics approach can be applied to study drug action of the intracellular amastigote form of T. cruzi in a parasite-host cell system. METHODS: We applied a metabolic fingerprinting approach (DI-MS and NMR) to evaluate metabolic changes induced by six different (candidate) drugs in a parasite-host cell system. In a second part of our study, we analyzed the impact of two drugs on polar metabolites, lipid and proteins to evaluate if affected pathways can be identified. RESULTS: Metabolic signatures, obtained by the fingerprinting approach, resulted in three different clusters. Two can be explained by already known of mode actions, whereas the three experimental drugs formed a separate cluster. Significant changes induced by drug action were observed in all the three metabolic fractions (polar metabolites, lipids and proteins). We identified a general impact on the TCA cycle, but no specific pathways could be attributed to drug action, which might be caused by a high percentage of common metabolome between a eukaryotic host cell and a eukaryotic parasite. Additionally, ion suppression effects due to differences in abundance between host cells and parasites may have occurred. CONCLUSION: We validated the metabolic fingerprinting approach to a complex host-cell parasite system. This technique can potentially be applied in the early stage of drug discovery and could help to prioritize early leads or reconfirmed hits for further development.


Assuntos
Interações Hospedeiro-Parasita , Metabolômica/métodos , Mioblastos/parasitologia , Proteômica/métodos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Metabolismo dos Lipídeos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Metaboloma , Mioblastos/metabolismo , Proteoma/química , Ratos , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade
19.
Infect Genet Evol ; 74: 103998, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401306

RESUMO

Chagas disease, a neglected tropical disease endemic in Latin America, is caused by the protozoan parasite Trypanosoma cruzi and is responsible for significant health impacts, especially in rural communities. The parasite is transmitted by insect vectors in the Triatominae subfamily and due to lack of vaccines and limited treatment options, vector control is the main way of controlling the disease. Knowing what vectors are feeding on directly enhances our understanding of the ecology and biology of the different vector species and can potentially aid in engaging communities in active disease control, a concept known as Ecohealth management. We evaluated bloodmeals in rural community, house-caught insect vectors previously evaluated for bloodmeals via DNA analysis as part of a larger collaborative project from three countries in Central America, including Guatemala. In addition to identifying bloodmeals in 100% of all samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) (n = 50), strikingly for 53% of these samples there was no evidence of a recent bloodmeal by DNA-PCR. As individual vectors often feed on multiple sources, we developed an enhanced detection pipeline, and showed the ability to quantify a bloodmeal using stable-isotope-containing synthetic references peptides, a first step in further exploration of species-specific bloodmeal composition. Furthermore, we show that a lower resolution mass spectrometer is sufficient to correctly identify taxa from bloodmeals, an important and strong attribute of our LC-MS/MS-based method, opening the door to using proteomics in countries where Chagas disease is endemic.


Assuntos
Ração Animal/análise , Doença de Chagas/transmissão , DNA/análise , Proteômica/métodos , Triatoma/patogenicidade , Trypanosoma cruzi/patogenicidade , Animais , América Central , Cromatografia Líquida , Feminino , Humanos , Proteínas de Insetos/metabolismo , Insetos Vetores/metabolismo , Insetos Vetores/parasitologia , Masculino , População Rural , Especificidade da Espécie , Espectrometria de Massas em Tandem , Triatoma/genética , Triatoma/metabolismo , Triatoma/parasitologia
20.
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
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