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1.
Exp Parasitol ; 210: 107834, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978394

RESUMO

Studies suggest that the dose of the standard benznidazole (BNZ) treatment regimen might be too high. We investigated the efficacy of BNZ 20 and 40 mg/kg/day compared with standard dose (100 mg/kg/day) to induce cure in mice infected with Trypanosoma cruzi Y strain in the acute and chronic phases of Chagas' disease. Our findings indicate that an experimental treatment with a BNZ low-dose (40 mg/kg/day) is similarly effective as the usual dose in the chronic mice model (100% of cure). In addition, the treatment in the chronic model of Chagas' disease presented better results than the acute model and colon appears to be a key tissue when it comes to evaluating treatment efficacy compared to blood and heart. Therefore, our data suggest the reconsideration of the current therapy, mainly in the chronic phase of the disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Animais , Sangue/parasitologia , Doença de Chagas/parasitologia , Doença Crônica , Colo/parasitologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Feminino , Coração/parasitologia , Imunossupressão , Camundongos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Nitroimidazóis/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologia
2.
Bull Entomol Res ; 110(1): 169-176, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31337451

RESUMO

Transmission of Trypanosma cruzi (Kinetoplastida: Trypanosomatidae) occurs when feces/urine of infected triatomines come into contact with mucous membranes or damaged skin, and this occurs mainly when insects defecate while feeding on the host. Thus, the vector competence of the triatomines is associated with their feeding and excretion/defecation behavior. This work studied for the first time the effect of T. cruzi infection on feeding and excretion/defecation patterns of Triatoma infestans (Hemiptera: Reduviidae). Uninfected and infected fifth-instar nymphs were fed ad libitum and their feeding behavior and defecations were registered during and after feeding. The feeding pattern did not show differences between the experimental groups. However, the infected nymphs began to defecate earlier, defecated in greater quantity and there was a greater proportion of defecating individuals compared to uninfected nymphs. These results show that T. cruzi affected the excretion/defecation pattern of T. infestans in a way that would increase the probability of contact between infective feces and the mammalian host.


Assuntos
Interações Hospedeiro-Parasita , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/transmissão , Defecação , Comportamento Alimentar , Triatoma/fisiologia
3.
Mem Inst Oswaldo Cruz ; 114: e190217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851215

RESUMO

The protozoan Trypanosoma cruzi has the ability to spontaneously secrete extracellular vesicles (EVs). In this paper, T. cruzi EVs derived from epimastigote forms were evaluated during interaction with triatomine bugs Rhodnius prolixus and Triatoma infestans. T. cruzi EVs were purified and artificially offered to the insects prior to infection with epimastigote forms. No effect of EVs was detected in the parasite counts in the guts of both vectors after 49-50 days. On the other hand, pre-feeding with EVs delayed parasite migration to rectum only in the gut in R. prolixus after 21-22 days. Those data suggest a possible role of T. cruzi EVs during the earlier events of infection in the invertebrate host.


Assuntos
Vesículas Extracelulares , Insetos Vetores/parasitologia , Intestinos/parasitologia , Rhodnius/parasitologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Interações Hospedeiro-Parasita/fisiologia , Trypanosoma cruzi/citologia
4.
PLoS Negl Trop Dis ; 13(11): e0007859, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751351

RESUMO

Host genetic factors have been suggested to play an important role in the susceptibility to Chagas disease. Given the influence of interleukin 18 (IL-18) in the development of the disease, in the present study, we analyzed three IL18 genetic variants (rs2043055, rs1946518, rs360719) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC), in different Latin America populations. Genetic data of 3,608 patients from Colombia, Bolivia, Argentina, and Brazil were meta-analyzed to validate previous findings with increased statistical power. Seropositive and seronegative individuals were compared for T. cruzi infection susceptibility. In the Colombian cohort, the allelic frequencies of the three variants showed a significant association, with adjustment for sex and age, and also after applying multiple testing adjustments. Among the Colombian and Argentinean cohorts, rs360719 showed a significant genetic effect in a fixed-effects meta-analysis after a Bonferroni correction (OR: 0.76, CI: 0.66-0.89, P = 0.001). For CCC, the rs2043055 showed an association with protection from cardiomyopathy in the Colombian cohort (OR: 0.79, CI: 0.64-0.99, P = 0.037), with adjustment for sex and age, and after applying multiple testing adjustments. The meta-analysis of the CCC vs. asymptomatic patients from the four cohorts showed no evidence of association. In conclusion, our results validated the association found previously in the Colombian cohort suggesting that IL18 rs360719 plays an important role in the susceptibility to T. cruzi infection and no evidence of association was found between the IL18 genetic variants and CCC in the Latin American population studied.


Assuntos
Doença de Chagas/genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Argentina , Bolívia , Brasil , Doença de Chagas/parasitologia , Estudos de Coortes , Colômbia , Feminino , Predisposição Genética para Doença , Hispano-Americanos/genética , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Trypanosoma cruzi/fisiologia , Adulto Jovem
5.
Parasit Vectors ; 12(1): 478, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31610815

RESUMO

BACKGROUND: Mepraia gajardoi and Mepraia spinolai are endemic triatomine vector species of Trypanosoma cruzi, a parasite that causes Chagas disease. These vectors inhabit arid, semiarid and Mediterranean areas of Chile. Mepraia gajardoi occurs from 18° to 25°S, and M. spinolai from 26° to 34°S. Even though both species are involved in T. cruzi transmission in the Pacific side of the Southern Cone of South America, no study has modelled their distributions at a regional scale. Therefore, the aim of this study is to estimate the potential geographical distribution of M. spinolai and M. gajardoi under current and future climate scenarios. METHODS: We used the Maxent algorithm to model the ecological niche of M. spinolai and M. gajardoi, estimating their potential distributions from current climate information and projecting their distributions to future climatic conditions under representative concentration pathways (RCP) 2.6, 4.5, 6.0 and 8.5 scenarios. Future predictions of suitability were constructed considering both higher and lower public health risk situations. RESULTS: The current potential distributions of both species were broader than their known ranges. For both species, climate change projections for 2070 in RCP 2.6, 4.5, 6.0 and 8.5 scenarios showed different results depending on the methodology used. The higher risk situation showed new suitable areas, but the lower risk situation modelled a net reduction in the future potential distribution areas of M. spinolai and M. gajardoi. CONCLUSIONS: The suitable areas for both species may be greater than currently known, generating new challenges in terms of vector control and prevention. Under future climate conditions, these species could modify their potential geographical range. Preventive measures to avoid accidental human vectorial transmission by wild vectors of T. cruzi become critical considering the uncertainty of future suitable areas projected in this study.


Assuntos
Doença de Chagas/transmissão , Mudança Climática , Insetos Vetores/fisiologia , Triatominae/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Área Sob a Curva , Doença de Chagas/epidemiologia , Chile/epidemiologia , Humanos , Umidade , Insetos Vetores/parasitologia , Modelos Biológicos , Filogeografia , Curva ROC , Chuva , Medição de Risco , Temperatura Ambiente , Triatominae/parasitologia
6.
Int J Mol Sci ; 20(19)2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31569452

RESUMO

Transforming growth factor beta (TGF-ß) is a determinant for inflammation and fibrosis in cardiac and skeletal muscle in Chagas disease. To determine its regulatory mechanisms, we investigated the response of Trypanosoma cruzi-infected cardiomyocytes (CM), cardiac fibroblasts (CF), and L6E9 skeletal myoblasts to TGF-ß. Cultures of CM, CF, and L6E9 were infected with T. cruzi (Y strain) and treated with TGF-ß (1-10 ng/mL, 1 h or 48 h). Fibronectin (FN) distribution was analyzed by immunofluorescence and Western blot (WB). Phosphorylated SMAD2 (PS2), phospho-p38 (p-p38), and phospho-c-Jun (p-c-Jun) signaling were evaluated by WB. CF and L6E9 showed an increase in FN from 1 ng/mL of TGF-ß, while CM displayed FN modulation only after 10 ng/mL treatment. CF and L6E9 showed higher PS2 levels than CM, while p38 was less stimulated in CF than CM and L6E9. T. cruzi infection resulted in localized FN disorganization in CF and L6E9. T. cruzi induced an increase in FN in CF cultures, mainly in uninfected cells. Infected CF cultures treated with TGF-ß showed a reduction in PS2 and an increase in p-p38 and p-c-Jun levels. Our data suggest that p38 and c-Jun pathways may be participating in the fibrosis regulatory process mediated by TGF-ß after T. cruzi infection.


Assuntos
Doença de Chagas/metabolismo , Doença de Chagas/parasitologia , Matriz Extracelular/metabolismo , Interações Hospedeiro-Patógeno , Fator de Crescimento Transformador beta/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Biomarcadores , Linhagem Celular , Células Cultivadas , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais
7.
PLoS Negl Trop Dis ; 13(9): e0007447, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557155

RESUMO

BACKGROUND: Chagas disease (CD) affects over 300,000 people in the United States, but fewer than 1% have been diagnosed and less than 0.3% have received etiological treatment. This is a significant public health concern because untreated CD can produce fatal complications. What factors prevent people with CD from accessing diagnosis and treatment in a nation with one of the world's most advanced healthcare systems? METHODOLOGY/PRINCIPAL FINDINGS: This analysis of barriers to diagnosis and treatment of CD in the US reflects the opinions of the authors more than a comprehensive discussion of all the available evidence. To enrich our description of barriers, we have conducted an exploratory literature review and cited the experience of the main US clinic providing treatment for CD. We list 34 barriers, which we group into four overlapping dimensions: systemic, comprising gaps in the public health system; structural, originating from political and economic inequalities; clinical, including toxicity of medications and diagnostic challenges; and psychosocial, encompassing fears and stigma. CONCLUSIONS: We propose this multidimensional framework both to explain the persistently low numbers of people with CD who are tested and treated and as a potential basis for organizing a public health response, but we encourage others to improve on our approach or develop alternative frameworks. We further argue that expanding access to diagnosis and treatment of CD in the US means asserting the rights of vulnerable populations to obtain timely, quality healthcare.


Assuntos
Doença de Chagas/epidemiologia , Assistência à Saúde , Doença de Chagas/diagnóstico , Doença de Chagas/parasitologia , Doença de Chagas/terapia , Humanos , Saúde Pública , Trypanosoma cruzi/fisiologia , Estados Unidos/epidemiologia
8.
Mem Inst Oswaldo Cruz ; 114: e180593, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433004

RESUMO

BACKGROUND: Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal transduction events during heart contraction-relaxation processes. Talin links integrins to the actin cytoskeleton and serves as a scaffold for the recruitment of other proteins, such as paxillin in focal adhesion formation and regulation. Chagasic cardiomyopathy is caused by infection by Trypanosoma cruzi and is a debilitating condition comprising extensive fibrosis, inflammation, cardiac hypertrophy and electrical alterations that culminate in heart failure. OBJECTIVES: Since mechanotransduction coordinates heart function, we evaluated the underlying mechanism implicated in the mechanical changes, focusing especially in mechanosensitive proteins and related signalling pathways during infection of cardiac cells by T. cruzi. METHODS: We investigated the effect of T. cruzi infection on the expression and distribution of talin/paxillin and associated proteins in mouse cardiomyocytes in vitro by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR). FINDINGS: Talin and paxillin spatial distribution in T. cruzi-infected cardiomyocytes in vitro were altered associated with a downregulation of these proteins and mRNAs levels at 72 h post-infection (hpi). Additionally, we observed an increase in the activation of the focal adhesion kinase (FAK) concomitant with increase in ß-1-integrin at 24 hpi. Finally, we detected a decrease in the activation of FAK at 72 hpi in T. cruzi-infected cultures. MAIN CONCLUSION: The results suggest that these changes may contribute to the mechanotransduction disturbance evidenced in chagasic cardiomyopathy.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Miócitos Cardíacos/parasitologia , Paxilina/metabolismo , Talina/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Western Blotting , Técnica Indireta de Fluorescência para Anticorpo , Immunoblotting , Mecanotransdução Celular/fisiologia , Camundongos , Reação em Cadeia da Polimerase em Tempo Real
9.
Diagn Microbiol Infect Dis ; 95(3): 114860, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31353066

RESUMO

Chagas disease is caused by Trypanosoma cruzi and affects about 7 million people worldwide. Benznidazole and nifurtimox have low efficacy and high toxicity. The present study was designed to identify the trypanocidal effect of (-)-α-Bisabolol (BIS) and investigate its mechanism. Epimastigotes and trypomastigotes were cultured with BIS and the viable cells were counted. BIS antiamastigote effect was evaluated using infected LLC-MK2 cells. MTT assay was performed to evaluate BIS cytotoxicity. Growth recovery was assessed to evaluate BIS effect after short times of exposure. BIS mechanism was investigated through flow cytometry, with 7-AAD and Annexin V-PE. DCFH-DA, rhodamine 123 (Rho123) and acridine orange (AO). Finally, enzymatic and computational assays were performed to identify BIS interaction with T. cruzi GAPDH (tcGAPDH). BIS showed an inhibitory effect on epimastigotes after all tested periods, as well on trypomastigotes. It caused cytotoxicity on LLC-MK2 cells at higher concentrations, with selectivity index (SeI) = 26.5. After treatment, infected cells showed a decrease in infected cells, the number of amastigotes per infected cell and the survival index (SuI). Growth recovery demonstrated that BIS effect causes rapid death of T. cruzi. Flow cytometry showed that BIS biological effect is associated with apoptosis induction, increase in cytoplasmic ROS and mitochondrial transmembrane potential, while reservosome swelling was observed at a late stage. Also, BIS action mechanism may be associated to tcGAPDH inhibition. Altogether, the results demonstrate that BIS causes cell death in Trypanosoma cruzi Y strain forms, with the involvement of apoptosis and oxidative stress and enzymatic inhibition.


Assuntos
/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Concentração Inibidora 50 , Macaca mulatta , Simulação de Acoplamento Molecular , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Trypanosoma cruzi/fisiologia
10.
Int J Infect Dis ; 87: 100-108, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357062

RESUMO

OBJECTIVE: Chagas disease affects over six million people, but less than 1% are diagnosed and treated. Complicated diagnostic processes are a major barrier. Colombia's previous diagnostic algorithm, using in-house tests, was difficult to scale up, creating significant access barriers for patients. A new algorithm using commercially manufactured immunoassays would potentially improve access, but these tests' performance in Colombian patients with Chagas disease is not well known. METHODS: We assessed seven commercially available assays. Samples (n=501), 93.8% originating from Colombia, were characterized as positive or negative based on standard procedure at the National Reference Laboratory. Performance characteristics were calculated for individual assays and hypothetical test pairings, then compared to the existing algorithm. RESULTS: Five of seven assays exhibited sensitivity >98% while six showed specificity >97%. A total antigen ELISA paired with a recombinant assay provided similar performance to the current diagnostic process. Six of six assays tested proved capable of detecting different Trypanosoma cruzi genetic lineages. CONCLUSIONS: The study indicated that several commercial assays accurately detect T. cruzi infection in Colombian patients. A simplified testing process with two commercial assays could perform comparably to the previous process, reducing cost and accessibility barriers and facilitating national scale-up.


Assuntos
Doença de Chagas/diagnóstico , Imunoensaio/métodos , Anticorpos Antiprotozoários/sangue , Doença de Chagas/sangue , Doença de Chagas/parasitologia , Colômbia , Humanos , Sensibilidade e Especificidade , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologia
11.
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
12.
Curr Med Chem ; 26(36): 6572-6589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218950

RESUMO

Trypanosomatids are a group of flagellated unicellular eukaryotes, causing serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites including differentiation between stages, proliferation, osmoregulation, oxidative stress and quorum sensing. Interestingly, its signaling pathway is quite different from that of mammals, including structurally different adenylyl cyclases, the shortage of orthologous effector proteins and the absence of G-protein-coupled-receptors, among others. These characteristics make the proteins involved in these transduction pathways good candidates for therapeutic targets. However, the identification of new unknown druggable targets involves extensive research time and is economically very expensive, making difficult the transition from basic research to the clinical phase. Trypanosomatid PDEs have characteristic binding pockets that allow for a differential inhibition from their human orthologs. Modification in the approved drugs for human to convert them into trypanocidal treatments could lead to more effective therapies, shorter lab time and lower costs. In view of the fact that kinetoplastid PDEs are highly conserved with their mammalian counterparts, and since there are already numerous drugs on the market against human PDEs, the drug repositioning approach is highly promising. The development of new technologies, higher government and industrial involvement and more scientists committed to basic investigation, are the key to ultimately find an effective treatment and cure for the neglected tropical diseases.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/fisiologia , Cálcio/fisiologia , Doença de Chagas/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Leishmania donovani/enzimologia , Leishmania donovani/fisiologia , Proteínas Quinases/fisiologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/fisiologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/fisiologia
13.
Parasitol Res ; 118(8): 2343-2351, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31236660

RESUMO

Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), although discovered more than a century ago, is still a not very well-elucidated aspect. Individuals in the chronic phase of the disease may present asymptomatic clinical form or symptomatologies related to the cardiac, digestive systems, or both (mixed clinical form). SNPs (single nucleotide polymorphisms) have been identified as important markers because they constitute about 90% of the variation in the human genome. One of them is localized to the ACAT-1 gene (cholesterol acyltransferase 1) (rs1044925) and has been linked to lipid disorders. Some studies have suggested the interaction between T. cruzi and the lipid metabolism of the host. Therefore, the objective of the present study was to evaluate the association between the ACAT-1 gene rs1044925 SNP in relation to clinical manifestations in patients with chronic Chagas disease. A total of 135 individuals with chronic Chagas disease, 86 (63.7%) asymptomatic individuals and 49 (36.3%) symptomatic patients (22 with cardiac clinical form, 18 with digestive form and 9 with mixed form) participated in the study. To evaluate the polymorphism, the PCR-RFLP technique were used. There was a significant difference and a higher frequency of AA and AC genotypes (p = 0.047 and p = 0.016, respectively) of the ACAT-1 gene in asymptomatic chagasic individuals. The result suggests a protective character of the AA and AC genotypes of the rs1044925 SNP in relation to the presence of symptomatic clinical manifestations of the disease in chronic chagasic individuals.


Assuntos
Doença de Chagas/genética , Polimorfismo de Nucleotídeo Único , Esterol O-Aciltransferase/genética , Idoso , Doenças Assintomáticas , Doença de Chagas/parasitologia , Doença Crônica , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Trypanosoma cruzi/fisiologia
14.
Microbes Infect ; 21(10): 485-489, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31247328

RESUMO

Cell invasion by Trypanosoma cruzi extracellular amastigotes involves different signaling pathways to induce phagocytosis-like mechanisms. Previous works indicated that PI3K/Akt, Src and Erk might be involved in EA invasion; however, participation of these molecules in this process remains elusive. Here, we observed that EA activated Akt, Erk but not Src. Interference of EA invasion with specific inhibitors corroborated this observation. Our results show that EA is capable of selectively triggering complex signaling pathways. Activation of PI3K/Akt and Erk, kinases related to actin cytoskeleton rearrangement and phagocytosis, reinforces the idea that T. cruzi EA subverts the phagocytic machinery during invasion.


Assuntos
Doença de Chagas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Trypanosoma cruzi/fisiologia , Doença de Chagas/parasitologia , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Células HeLa , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
15.
PLoS Negl Trop Dis ; 13(5): e0007392, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107905

RESUMO

BACKGROUND: Sexual reproduction provides an evolutionary advantageous mechanism that combines favorable mutations that have arisen in separate lineages into the same individual. This advantage is especially pronounced in microparasites as allelic reassortment among individuals caused by sexual reproduction promotes allelic diversity at immune evasion genes within individuals which is often essential to evade host immune systems. Despite these advantages, many eukaryotic microparasites exhibit highly-clonal population structures suggesting that genetic exchange through sexual reproduction is rare. Evidence supporting clonality is particularly convincing in the causative agent of Chagas disease, Trypanosoma cruzi, despite equally convincing evidence of the capacity to engage in sexual reproduction. METHODOLOGY/ PRINCIPLE FINDINGS: In the present study, we investigated two hypotheses that can reconcile the apparent contradiction between the observed clonal population structure and the capacity to engage in sexual reproduction by analyzing the genome sequences of 123 T. cruzi isolates from a natural population in Arequipa, Peru. The distribution of polymorphic markers within and among isolates provides clear evidence of the occurrence of sexual reproduction. Large genetic segments are rearranged among chromosomes due to crossing over during meiosis leading to a decay in the genetic linkage among polymorphic markers compared to the expectations from a purely asexually-reproducing population. Nevertheless, the population structure appears clonal due to a high level of inbreeding during sexual reproduction which increases homozygosity, and thus reduces diversity, within each inbreeding lineage. CONCLUSIONS/ SIGNIFICANCE: These results effectively reconcile the apparent contradiction by demonstrating that the clonal population structure is derived not from infrequent sex in natural populations but from high levels of inbreeding. We discuss epidemiological consequences of this reproductive strategy on genome evolution, population structure, and phenotypic diversity of this medically important parasite.


Assuntos
Doença de Chagas/parasitologia , Trypanosoma cruzi/fisiologia , Genoma de Protozoário , Genótipo , Humanos , Reprodução , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento
16.
Parasit Vectors ; 12(1): 219, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068226

RESUMO

BACKGROUND: Little is known about how human disease vectors will modify their life history patterns and survival capacity as a result of climate change. One case is that of Chagas disease, which has triatomine bugs and Trypanosoma cruzi as vectors and parasite, respectively. This work aimed to determine: (i) the activity of the prophenoloxidase system (prophenoloxidase and phenoloxidase activity, two indicators of immune ability) in three intestine regions (anterior midgut, posterior midgutand rectum) of the triatomine bug Meccus pallidipennis under three temperature conditions (20 °C, 30 °C and 34 °C) against two T. cruzi strains [ITRI/MX/14/CHIL (Chilpancingo) and ITRI/MX/12/MOR (Morelos)], and (ii) whether vector survival varies under these three temperatures after infection by these T. cruzi strains. RESULTS: Our results indicate that prophenoloxidase activity was lower at higher temperatures, that the level of prophenoloxidase activity elicited by each strain was different (higher in Chilpancingo than in Morelos strains), and that prophenoloxidase activity was more intense in the anterior midgut than in the posterior midgut or rectum. Survival rates were lower in insects maintained at higher temperatures and infected by Chilpancingo strains. CONCLUSIONS: These results indicate that climate change could lead to lower prophenoloxidase activity and survival rates in triatomines when infected with different T. cruzi strains, which could reduce the vector capacity of M. pallidipennis.


Assuntos
Catecol Oxidase/metabolismo , Mudança Climática , Precursores Enzimáticos/metabolismo , Temperatura Ambiente , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Feminino , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/parasitologia , Insetos Vetores/enzimologia , Insetos Vetores/parasitologia , Masculino , Triatoma/enzimologia
17.
PLoS Negl Trop Dis ; 13(5): e0007383, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059501

RESUMO

Triatomine vectors transmit Trypanosoma cruzi, the etiological agent of Chagas disease in humans. Transmission to humans typically occurs when contaminated triatomine feces come in contact with the bite site or mucosal membranes. In the Southern Cone of South America, where the highest burden of disease exists, Triatoma infestans is the principal vector for T. cruzi. Recent studies of other vector-borne illnesses have shown that arthropod microbiota influences the ability of infectious agents to colonize the insect vector and transmit to the human host. This has garnered attention as a potential control strategy against T. cruzi, as vector control is the main tool of Chagas disease prevention. Here we characterized the microbiota in T. infestans feces of both wild-caught and laboratory-reared insects and examined the relationship between microbial composition and T. cruzi infection using highly sensitive high-throughput sequencing technology to sequence the V3-V4 region of the 16S ribosomal RNA gene on the MiSeq Illumina platform. We collected 59 wild (9 with T. cruzi infection) and 10 lab-reared T. infestans (4 with T. cruzi infection) from the endemic area of Arequipa, Perú. Wild T. infestans had greater hindgut bacterial diversity than laboratory-reared bugs. Microbiota of lab insects comprised a subset of those identified in their wild counterparts, with 96 of the total 124 genera also observed in laboratory-reared insects. Among wild insects, variation in bacterial composition was observed, but time and location of collection and development stage did not explain this variation. T. cruzi infection in lab insects did not affect α- or ß-diversity; however, we did find that the ß-diversity of wild insects differed if they were infected with T. cruzi and identified 10 specific taxa that had significantly different relative abundances in infected vs. uninfected wild T. infestans (Bosea, Mesorhizobium, Dietzia, and Cupriavidus were underrepresented in infected bugs; Sporosarcina, an unclassified genus of Porphyromonadaceae, Nestenrenkonia, Alkalibacterium, Peptoniphilus, Marinilactibacillus were overrepresented in infected bugs). Our findings suggest that T. cruzi infection is associated with the microbiota of T. infestans and that inferring the microbiota of wild T. infestans may not be possible through sampling of T. infestans reared in the insectary.


Assuntos
Bactérias/isolamento & purificação , Doença de Chagas/transmissão , Insetos Vetores/microbiologia , Microbiota , Triatoma/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Doença de Chagas/parasitologia , DNA Bacteriano/genética , Fezes/microbiologia , Trato Gastrointestinal/microbiologia , Humanos , Insetos Vetores/parasitologia , Insetos Vetores/fisiologia , Laboratórios , Filogenia , RNA Ribossômico 16S/genética , Triatoma/parasitologia , Triatoma/fisiologia , Trypanosoma cruzi/fisiologia
18.
PLoS Negl Trop Dis ; 13(5): e0007413, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31145733

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection.


Assuntos
Anticorpos Antiprotozoários/imunologia , Cardiomiopatia Chagásica/imunologia , Vacinas Protozoárias/administração & dosagem , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/prevenção & controle , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Interferon gama/genética , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/patologia , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/patologia , Parasitemia/prevenção & controle , Vacinas Protozoárias/imunologia , Células Th1/imunologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Vacinação
19.
Parasit Vectors ; 12(1): 240, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097007

RESUMO

BACKGROUND: Theory predicts that parasites can affect and thus drive their hosts' niche. Testing this prediction is key, especially for vector-borne diseases including Chagas disease. Here, we examined the niche use of seven triatomine species that occur in Mexico, based on whether they are infected or not with Trypanosoma cruzi, the vectors and causative parasites of Chagas disease, respectively. Presence data for seven species of triatomines (Triatoma barberi, T. dimidiata, T. longipennis, T. mazzottii, T. pallidipennis, T. phyllosoma and T. picturata) were used and divided into populations infected and not infected by T. cruzi. Species distribution models were generated with Maxent 3.3.3k. Using distribution models, niche analysis tests of amplitude and distance to centroids were carried out for infected vs non-infected populations within species. RESULTS: Infected populations of bugs of six out of the seven triatomine species showed a reduced ecological space compared to non-infected populations. In all but one case (T. pallidipennis), the niche used by infected populations was close to the niche centroid of its insect host. CONCLUSIONS: Trypanosoma cruzi may have selected for a restricted niche amplitude in triatomines, although we are unaware of the underlying reasons. Possibly the fact that T. cruzi infection bears a fitness cost for triatomines is what narrows the niche breadth of the insects. Our results imply that Chagas control programmes should consider whether bugs are infected in models of triatomine distribution.


Assuntos
Ecossistema , Triatoma/fisiologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Insetos Vetores/parasitologia , Insetos Vetores/fisiologia , México
20.
Int J Food Microbiol ; 301: 34-40, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31082698

RESUMO

The most important mode of transmission causing outbreaks of Chagas disease in the Amazon region is the oral route due to the ingestion of contaminated food. Herein, prevention methods for foodborne diseases caused by Trypanosoma cruzi, namely, sanitization, thermal treatment were investigated and the use of reverse transcription PCR (RT-PCR) amplification for the mRNA-based detection of viable T. cruzi in açai, was developed. Three T. cruzi strains (T. cruzi I, T. cruzi III and Y) were used in the present study. The Amazonian strains T. cruzi I (425) and T. cruzi III (370) showed higher resistance to sodium hypochlorite treatment and heat treatment than the reference strain Y. The blanching of fruits (70 ±â€¯1 °C for 10 s) and pasteurization of juice (82.5 °C for 1 min) efficiently eliminated T. cruzi in food matrices. Additionally, a method that uses RT-PCR amplification of mRNA was developed for the detection of viable T. cruzi in açai, which could play a role in examining food samples, ensuring consumer health, and reducing this foodborne disease.


Assuntos
Doença de Chagas/prevenção & controle , Desinfecção , Microbiologia de Alimentos/métodos , Doenças Transmitidas por Alimentos/prevenção & controle , Temperatura Alta , Reação em Cadeia da Polimerase , Animais , Humanos , Controle de Qualidade , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/fisiologia
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