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1.
Parasitol Int ; 87: 102530, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34929405

RESUMO

Trypanosoma cruzi triggers a progressive myocarditis in mammalians through activation and recruitment of leukocytes and release of inflammatory mediators. The chemokine CX3CL1 has been highlighted for its potential role in the parasite controlling in end-pathological status of infected hosts. This study investigated the systemic and cardiac release of CX3CL1 in experimental T. cruzi infection and how this chemokine correlates with endothelin-1 and TNF. Male Fisher rats (n = 20) were infected, or not, by the Y strain of T. cruzi and parasitemia was daily evaluated and immunoassays performed in the cardiac tissue macerated supernatant and in serum to evaluate CX3CL1, endothelin, and TNF production on days 5 and 15 of infection. T. cruzi infection induced a higher serum and cardiac production of these mediators on days 5 and 15 of infection. In both periods of infection, respectively, CX3CL1 showed a positive correlation with TNF (r = 0.833, p < 0.001 and r = 0.723, p < 0.001) and endothelin-1 (r = 0.801, p < 0.05 and r = 0.857, p < 0.001), which reinforce its participation in the T. cruzi-induced myocarditis development.


Assuntos
Doença de Chagas/complicações , Quimiocina CX3CL1/metabolismo , Miocardite/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Endotelina-1/metabolismo , Masculino , Ratos , Trypanosoma cruzi/classificação
2.
Sci Rep ; 11(1): 23884, 2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903840

RESUMO

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi parasite with an estimated 70 million people at risk. Traditionally, parasite presence in triatomine vectors is detected through optical microscopy which can be low in sensitivity or molecular techniques which can be costly in endemic countries. The aim of this study was to evaluate the ability of a reagent-free technique, the Near Infrared Spectroscopy (NIRS) for rapid and non-invasive detection of T. cruzi in Triatoma infestans body parts and in wet/dry excreta samples of the insect. NIRS was 100% accurate for predicting the presence of T. cruzi infection Dm28c strain (TcI) in either the midgut or the rectum and models developed from either body part could predict infection in the other part. Models developed to predict infection in excreta samples were 100% accurate for predicting infection in both wet and dry samples. However, models developed using dry excreta could not predict infection in wet samples and vice versa. This is the first study to report on the potential application of NIRS for rapid and non-invasive detection of T. cruzi infection in T. infestans in the laboratory. Future work should demonstrate the capacity of NIRS to detect T. cruzi in triatomines originating from the field.


Assuntos
Insetos Vetores/parasitologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Triatoma/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Fezes/parasitologia , Intestinos/parasitologia , Limite de Detecção , Espectroscopia de Luz Próxima ao Infravermelho/normas , Trypanosoma cruzi/isolamento & purificação
3.
Front Immunol ; 12: 780810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899745

RESUMO

Background: Trypanosomatids are protozoa responsible for a wide range of diseases, with emphasis on Chagas Disease (CD) and Leishmaniasis, which are in the list of most relevant Neglected Tropical Diseases (NTD) according to World Health Organization (WHO). During the infectious process, immune system is immediately activated, and parasites can invade nucleated cells through a broad diversity of receptors. The complement system - through classical, alternative and lectin pathways - plays a role in the first line of defense against these pathogens, acting in opsonization, phagocytosis and lysis of parasites. Genetic modifications in complement genes, such as Single Nucleotide Polymorphisms (SNPs), can influence host susceptibility to these parasites and modulate protein expression. Methods: In March and April 2021, a literature search was conducted at the PubMed and Google Scholar databases and the reference lists obtained were verified. After applying the inclusion and exclusion criteria, the selected studies were evaluated and scored according to eleven established criteria regarding their thematic approach and design, aiming at the good quality of publications. Results: Twelve papers were included in this systematic review: seven investigating CD and five focusing on Leishmaniasis. Most articles presented gene and protein approaches, careful determination of experimental groups, and adequate choice of experimental techniques, although several of them were not up-to-date. Ten studies explored the association of polymorphisms and haplotypes with disease progression, with emphasis on lectin complement pathway genes. Decreased and increased patient serum protein levels were associated with susceptibility to CD and Visceral Leishmaniasis, respectively. Conclusion: This systematic review shows the influence of genetic alterations in complement genes on the progression of several infectious diseases, with a focus on conditions caused by trypanosomatids, and contributes suggestions and evidence to improve experimental design in future research proposals.


Assuntos
Doença de Chagas/parasitologia , Ativação do Complemento/genética , Proteínas do Sistema Complemento/genética , Variação Genética , Leishmania/patogenicidade , Leishmaniose/parasitologia , Trypanosoma cruzi/patogenicidade , Doença de Chagas/genética , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Progressão da Doença , Predisposição Genética para Doença , Interações Hospedeiro-Parasita , Humanos , Leishmania/imunologia , Leishmaniose/genética , Leishmaniose/imunologia , Leishmaniose/metabolismo , Fenótipo , Medição de Risco , Fatores de Risco , Trypanosoma cruzi/imunologia
4.
J Infect Dev Ctries ; 15(11): 1714-1723, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34898501

RESUMO

INTRODUCTION: Chagas disease is a neglected disease in the American continent. The southern Mexican state of Chiapas has the highest incidence rate of Chagas disease in the country. The disease, mainly caused by Tripanosoma cruzi in Mexico, is more prevalent in males than in females but the scientific basis for the sex-related tropism is not completely understood. The objective of this study was to evaluate the pathogenicity of a T. cruzi strain in mice of both sexes and to assess certain elements of the immune response in the infected animals. METHODOLOGY: Triatomines bugs were searched at Los Mezcales, Chiapas, Mexico and T. cruzi was identified by PCR and sequencing. A T. cruzi strain was isolated from the feces of triatomines bugs. Mice were infected with the strain and the virulence of the T. cruzi strain as well as the immune response against the infection was compared in male versus female mice. RESULTS: T. dimidiata was identified in all dwellings. 42.9% of the bugs were infected with T. cruzi lineage TcI. Male mice exhibited higher parasitemia than females, and developed leukopenia and lower levels of anti-T. cruzi antibodies compared to female mice. CONCLUSIONS: The identification of the T. cruzi strain in this endemic region of Mexico revealed that male mice are prone to this infectious protozoo, in addition to manifesting a deficient immune response against infection. These findings may explain the greater number of cases of Chagas disease among men in this endemic region of Latin America.


Assuntos
Doença de Chagas/epidemiologia , Imunidade , Trypanosoma cruzi/patogenicidade , Adolescente , Adulto , Animais , Doença de Chagas/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Insetos Vetores/imunologia , Masculino , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Fatores Sexuais , Trypanosoma cruzi/isolamento & purificação , Adulto Jovem
5.
Biochem J ; 478(21): 3891-3903, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34661234

RESUMO

The pathogenic protist Trypanosoma cruzi uses kissing bugs as invertebrate hosts that vectorize the infection among mammals. This parasite oxidizes proline to glutamate through two enzymatic steps and one nonenzymatic step. In insect vectors, T. cruzi differentiates from a noninfective replicating form to nonproliferative infective forms. Proline sustains this differentiation, but to date, a link between proline metabolism and differentiation has not been established. In T. cruzi, the enzymatic steps of the proline-glutamate oxidation pathway are catalyzed exclusively by the mitochondrial enzymes proline dehydrogenase [TcPRODH, EC: 1.5.5.2] and Δ1-pyrroline-5-carboxylate dehydrogenase [TcP5CDH, EC: 1.2.1.88]. Both enzymatic steps produce reducing equivalents that are able to directly feed the mitochondrial electron transport chain (ETC) and thus produce ATP. In this study, we demonstrate the contribution of each enzyme of the proline-glutamate pathway to ATP production. In addition, we show that parasites overexpressing these enzymes produce increased levels of H2O2, but only those overexpressing TcP5CDH produce increased levels of superoxide anion. We show that parasites overexpressing TcPRODH, but not parasites overexpressing TcP5CDH, exhibit a higher rate of differentiation into metacyclic trypomastigotes in vitro. Finally, insect hosts infected with parasites overexpressing TcPRODH showed a diminished parasitic load but a higher percent of metacyclic trypomastigotes, when compared with controls. Our data show that parasites overexpressing both, PRODH and P5CDH had increased mitochondrial functions that orchestrated different oxygen signaling, resulting in different outcomes in relation to the efficiency of parasitic differentiation in the invertebrate host.


Assuntos
Doença de Chagas/parasitologia , Mitocôndrias/metabolismo , Prolina Oxidase/metabolismo , Rhodnius/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Diferenciação Celular
7.
Parasit Vectors ; 14(1): 519, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34625109

RESUMO

BACKGROUND: Colombia's National Army is one of the largest military institutions in the country based on the number of serving members and its presence throughout the country. There have been reports of cases of acute or chronic cases of Chagas disease among active military personnel. These may be the result of military-associated activities performed in jungles and other endemic areas or the consequence of exposure to Trypanosoma cruzi inside military establishments/facilities located in endemic areas. The aim of the present study was to describe the circulation of T. cruzi inside facilities housing four training and re-training battalions [Battalions of Instruction, Training en Re-training (BITERs)] located in municipalities with historical reports of triatomine bugs and Chagas disease cases. An entomological and faunal survey of domestic and sylvatic environments was conducted inside each of these military facilities. METHODS: Infection in working and stray dogs present in each BITER location was determined using serological and molecular tools, and T. cruzi in mammal and triatomine bug samples was determined by PCR assay. The PCR products of the vertebrate 12S rRNA gene were also obtained and subjected to Sanger sequencing to identify blood-feeding sources. Finally, we performed a geospatial analysis to evaluate the coexistence of infected triatomines and mammals with the military personal inside of each BITER installation. RESULTS: In total, 86 specimens were collected: 82 Rhodnius pallescens, two Rhodnius prolixus, one Triatoma dimidiata and one Triatoma maculata. The overall T. cruzi infection rate for R. pallescens and R. prolixus was 56.1 and 100% respectively, while T. dimidiata and T. maculata were not infected. Eight feeding sources were found for the infected triatomines, with opossum and humans being the most frequent sources of feeding (85.7%). Infection was most common in the common opossum Didelphis marsupialis, with infection levels of 77.7%. Sylvatic TcI was the most frequent genotype, found in 80% of triatomines and 75% of D. marsupialis. Of the samples collected from dogs (n = 52), five (9.6%; 95% confidence interval: 3.20-21.03) were seropositive based on two independent tests. Four of these dogs were creole and one was a working dog. The spatial analysis revealed a sympatry between infected vectors and mammals with the military population. CONCLUSIONS: We have shown a potential risk of spillover of sylvatic T. cruzi transmission to humans by oral and vectorial transmission in two BITER installations in Colombia. The results indicate that installations where 100,000 active military personnel carry out training activities should be prioritized for epidemiological surveillance of Chagas disease.


Assuntos
Doença de Chagas/transmissão , Habitação , Insetos Vetores/parasitologia , Militares/estatística & dados numéricos , Ensino , Triatominae/parasitologia , Trypanosoma cruzi/patogenicidade , Zoonoses/parasitologia , Animais , Antígenos de Protozoários/sangue , Antígenos de Protozoários/imunologia , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Colômbia/epidemiologia , Cães , Feminino , Genótipo , Humanos , Masculino , Mamíferos/parasitologia , Fatores de Risco , Triatominae/genética , Trypanosoma cruzi/imunologia , Zoonoses/prevenção & controle , Zoonoses/transmissão
8.
Exp Parasitol ; 230: 108159, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34563508

RESUMO

Trypanosoma rangeli is a non-virulent hemoflagellate parasite infecting humans, wild and domestic mammals in Central and Latin America. The share of genotypic, phenotypic, and biological similarities with the virulent, human-infective T. cruzi and T. brucei, allows comparative studies on mechanisms of pathogenesis. In this study, investigation of the T. rangeli Arginine Kinase (TrAK) revealed two highly similar copies of the AK gene in this taxon, and a distinct expression profile and activity between replicative and infective forms. Although TrAK expression seems stable during epimastigotes growth, the enzymatic activity increases during the exponential growth phase and decreases from the stationary phase onwards. No differences were observed in activity or expression levels of TrAK during in vitro differentiation from epimastigotes to infective forms, and no detectable AK expression was observed for blood trypomastigotes. Overexpression of TrAK by T. rangeli showed no effects on the in vitro growth pattern, differentiation to infective forms, or infectivity to mice and triatomines. Although differences in TrAK expression and activity were observed among T. rangeli strains from distinct genetic lineages, our results indicate an up-regulation during parasite replication and putative post-translational myristoylation of this enzyme. We conclude that up-regulation of TrAK activity in epimastigotes appears to improve proliferation fitness, while reduced TrAK expression in blood trypomastigotes may be related to short-term and subpatent parasitemia in mammalian hosts.


Assuntos
Arginina Quinase/metabolismo , Processamento de Proteína Pós-Traducional , Trypanosoma cruzi/enzimologia , Trypanosoma rangeli/enzimologia , Sequência de Aminoácidos , Animais , Arginina Quinase/biossíntese , Arginina Quinase/classificação , Arginina Quinase/genética , Western Blotting , DNA de Protozoário/isolamento & purificação , Eletroforese em Gel Bidimensional , Feminino , Flagelos/enzimologia , Técnica Indireta de Fluorescência para Anticorpo , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Alinhamento de Sequência , Trypanosoma cruzi/classificação , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Trypanosoma rangeli/classificação , Trypanosoma rangeli/genética , Trypanosoma rangeli/patogenicidade , Regulação para Cima , Virulência
9.
Biomolecules ; 11(9)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34572535

RESUMO

Calcineurin (CaN) is present in all eukaryotic cells, including intracellular trypanosomatid parasites such as Trypanosoma cruzi (Tc) and Leishmania spp. (Lspp). In this study, we performed an in silico analysis of the CaN subunits, comparing them with the human (Hs) and looking their structure, post-translational mechanisms, subcellular distribution, interactors, and secretion potential. The differences in the structure of the domains suggest the existence of regulatory mechanisms and differential activity between these protozoa. Regulatory subunits are partially conserved, showing differences in their Ca2+-binding domains and myristoylation potential compared with human CaN. The subcellular distribution reveals that the catalytic subunits TcCaNA1, TcCaNA2, LsppCaNA1, LsppCaNA1_var, and LsppCaNA2 associate preferentially with the plasma membrane compared with the cytoplasmic location of HsCaNAα. For regulatory subunits, HsCaNB-1 and LsppCaNB associate preferentially with the nucleus and cytoplasm, and TcCaNB with chloroplast and cytoplasm. Calpain cleavage sites on CaNA suggest differential processing. CaNA and CaNB of these trypanosomatids have the potential to be secreted and could play a role in remote communication. Therefore, this background can be used to develop new drugs for protozoan pathogens that cause neglected disease.


Assuntos
Calcineurina/metabolismo , Simulação por Computador , Espaço Intracelular/parasitologia , Leishmania/patogenicidade , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/patogenicidade , Sequência de Aminoácidos , Calcineurina/química , Calpaína/metabolismo , Sequência Conservada , Humanos , Imunofilinas/metabolismo , Imunossupressores/farmacologia , Ácido Mirístico/metabolismo , Fosforilação , Domínios Proteicos , Subunidades Proteicas/metabolismo , Proteínas de Protozoários/química , Frações Subcelulares/metabolismo
10.
Front Cell Infect Microbiol ; 11: 696719, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336720

RESUMO

Resistance or susceptibility to T. cruzi infection is dependent on the host immunological profile. Innate immune receptors, such as Toll-like receptors (TLRs/TLR2, TLR4, TLR7, and TLR9) and Nod-like receptors (NLRs/NOD1 and NLRP3 inflammasome) are involved with the resistance against acute experimental T. cruzi infection. Here, we evaluated the impact of T. cruzi virulence on the expression of innate immune receptors and its products in mice. For that, we used six T. cruzi strains/isolates that showed low (AM64/TcIV and 3253/Tc-V), medium (PL1.10.14/TcIII and CL/TcVI), or high (Colombian/Tc-I and Y/TcII) virulence and pathogenicity to the vertebrate host and belonging to the six discrete typing units (DTUs)-TcI to TcVI. Parasitemia, mortality, and myocarditis were evaluated and correlated to the expression of TLRs, NLRs, adapter molecules, cytokines, and iNOS in myocardium by real time PCR. Cytokines (IL-1ß, IL-12, TNF-α, and IFN-γ) were quantified in sera 15 days after infection. Our data indicate that high virulent strains of T. cruzi, which generate high parasitemia, severe myocarditis, and 100% mortality in infected mice, inhibit the expression of TLR2, TLR4, TLR9, TRIF, and Myd88 transcripts, leading to a low IL-12 production, when compared to medium and low virulent T. cruzi strains. On the other hand, the high virulent T. cruzi strains induce the upregulation of NLRP3, caspase-1, IL-1ß, TNF-α, and iNOS mRNA in heart muscle, compared to low and medium virulent strains, which may contribute to myocarditis and death. Moreover, high virulent strains induce higher levels of IL-1ß and TNF-α in sera compared to less virulent parasites. Altogether the data indicate that differential TLR and NLR expression in heart muscle is correlated with virulence and pathogenicity of T cruzi strains. A better knowledge of the immunological mechanisms involved in resistance to T. cruzi infection is important to understand the natural history of Chagas disease, can lead to identification of immunological markers and/or to serve as a basis for alternative therapies.


Assuntos
Doença de Chagas , Imunidade Inata , Miocárdio/imunologia , Trypanosoma cruzi , Animais , Caspase 1 , Coração , Camundongos , Trypanosoma cruzi/patogenicidade , Virulência
11.
PLoS Pathog ; 17(8): e1009864, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34424944

RESUMO

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. The mechanism of pathogenesis is poorly understood and the lack of a robust, predictive animal model has held back research. We screened a series of mouse models using gastrointestinal tracer assays and in vivo infection imaging systems to discover a subset exhibiting chronic digestive transit dysfunction and significant retention of faeces in both sated and fasted conditions. The colon was a specific site of both tissue parasite persistence, delayed transit and dramatic loss of myenteric neurons as revealed by whole-mount immunofluorescence analysis. DCD mice therefore recapitulated key clinical manifestations of human disease. We also exploited dual reporter transgenic parasites to home in on locations of rare chronic infection foci in the colon by ex vivo bioluminescence imaging and then used fluorescence imaging in tissue microdomains to reveal co-localisation of infection and enteric nervous system lesions. This indicates that long-term T. cruzi-host interactions in the colon drive DCD pathogenesis, suggesting that the efficacy of anti-parasitic chemotherapy against chronic disease progression warrants further pre-clinical investigation.


Assuntos
Doença de Chagas/complicações , Modelos Animais de Doenças , Trato Gastrointestinal/parasitologia , Pseudo-Obstrução Intestinal/patologia , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Doença Crônica , Feminino , Pseudo-Obstrução Intestinal/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos SCID
12.
Cell Death Dis ; 12(7): 692, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34247195

RESUMO

Chagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/-, Bim-/- mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim-/- mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/- mice. At the peak of parasitemia, peritoneal macrophages of Bim-/- mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim-/- splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim-/- mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim-/- mice and place Bim as an important protein in the control of T. cruzi infections.


Assuntos
Proteína 11 Semelhante a Bcl-2/deficiência , Doença de Chagas/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Proteína 11 Semelhante a Bcl-2/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/parasitologia , Células Cultivadas , Doença de Chagas/genética , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Parasita , Interferon gama/metabolismo , Interleucina-6/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Carga Parasitária , Baço/imunologia , Baço/metabolismo , Baço/parasitologia , Fatores de Tempo , Trypanosoma cruzi/imunologia
13.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203228

RESUMO

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitrofurazona/análogos & derivados , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Feminino , Medições Luminescentes , Camundongos , Camundongos Endogâmicos BALB C , Nitrofurazona/farmacologia , Nitrofurazona/uso terapêutico
14.
J Med Microbiol ; 70(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34184983

RESUMO

The nonpolar lipids present in cells are mainly triacylglycerols and steryl esters. When cells are provided with an abundance of nutrients, these storage lipids accumulate. As large quantities of nonpolar lipids cannot be integrated into membranes, they are isolated from the cytosolic environment in lipid droplets. As specialized, inducible cytoplasmic organelles, lipid droplets have functions beyond the regulation of lipid metabolism, in cell signalling and activation, membrane trafficking and control of inflammatory mediator synthesis and secretion. Pathogens, including fungi, viruses, parasites, or intracellular bacteria can induce and may benefit from lipid droplets in infected cells. Here we review biogenesis of lipid droplets as well as the role of lipid droplets in the pathogenesis of selected viruses, bacteria, protists and yeasts.


Assuntos
Bactérias/patogenicidade , Gotículas Lipídicas/fisiologia , Vírus/patogenicidade , Leveduras/patogenicidade , Metabolismo dos Lipídeos , Plasmodium falciparum/patogenicidade , Trypanosoma cruzi/patogenicidade
15.
Sci Rep ; 11(1): 12306, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112903

RESUMO

Chagas disease remains a major neglected disease in Colombia. We aimed to characterize Trypanosoma cruzi transmission networks in the Sierra Nevada de Santa Marta (SNSM) region, to shed light on disease ecology and help optimize control strategies. Triatomines were collected in rural communities and analyzed for blood feeding sources, parasite diversity and gut microbiota composition through a metagenomic and deep sequencing approach. Triatoma dimidiata predominated, followed by Rhodnius prolixus, Triatoma maculata, Rhodnius pallescens, Panstrongylus geniculatus and Eratyrus cuspidatus. Twenty-two species were identified as blood sources, resulting in an integrated transmission network with extensive connectivity among sylvatic and domestic host species. Only TcI parasites were detected, predominantly from TcIb but TcIa was also reported. The close relatedness of T. cruzi strains further supported the lack of separate transmission cycles according to habitats or triatomine species. Triatomine microbiota varied according to species, developmental stage and T. cruzi infection. Bacterial families correlated with the presence/absence of T. cruzi were identified. In conclusion, we identified a domestic transmission cycle encompassing multiple vector species and tightly connected with sylvatic hosts in the SNSM region, rather than an isolated domestic transmission cycle. Therefore, integrated interventions targeting all vector species and their contact with humans should be considered.


Assuntos
Microbioma Gastrointestinal/genética , Variação Genética , Triatoma/genética , Triatominae/genética , Animais , Doença de Chagas/genética , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Genótipo , Humanos , Insetos Vetores/genética , Grupos Populacionais , Rhodnius/patogenicidade , Triatoma/classificação , Triatominae/parasitologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade
16.
PLoS One ; 16(5): e0252071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34015050

RESUMO

Attalea palms provide primary habitat to Rhodnius spp., vectors of Trypanosoma cruzi. Flying from palms, these blood-sucking bugs often invade houses and can infect people directly or via food contamination. Chagas disease (CD) risk may therefore increase when Attalea palms thrive near houses. For example, Attalea dominate many deforested landscapes of eastern Amazonia, where acute-CD outbreaks are disturbingly frequent. Despite this possible link between deforestation and CD risk, the population-level responses of Amazonian Attalea and their resident Rhodnius to anthropogenic landscape disturbance remain largely uncharted. We studied adult Attalea palms in old-growth forest (OGF), young secondary forest (YSF), and cattle pasture (CP) in two localities of eastern Amazonia. We recorded 1856 Attalea along 10 transects (153.6 ha), and detected infestation by Rhodnius spp. in 18 of 280 systematically-sampled palms (33 bugs caught). Distance-sampling models suggest that, relative to OGF, adult Attalea density declined by 70-80% in CP and then recovered in YSF. Site-occupancy models estimate a strong positive effect of deforestation on palm-infestation odds (ßCP-infestation = 4.82±1.14 SE), with a moderate decline in recovering YSF (ßYSF-infestation = 2.66±1.10 SE). Similarly, N-mixture models suggest that, relative to OGF, mean vector density sharply increased in CP palms (ßCP-density = 3.20±0.62 SE) and then tapered in YSF (ßYSF-density = 1.61±0.76 SE). Together, these results indicate that disturbed landscapes may support between ~2.5 (YSF) and ~5.1 (CP) times more Attalea-dwelling Rhodnius spp. per unit area than OGF. We provide evidence that deforestation may favor palm-dwelling CD vectors in eastern Amazonia. Importantly, our landscape-disturbance effect estimates explicitly take account of (i) imperfect palm and bug detection and (ii) the uncertainties about infestation and vector density arising from sparse bug data. These results suggest that incorporating landscape-disturbance metrics into the spatial stratification of transmission risk could help enhance CD surveillance and prevention in Amazonia.


Assuntos
Doença de Chagas/parasitologia , Insetos Vetores/parasitologia , Rhodnius/patogenicidade , Trypanosoma cruzi/patogenicidade , Animais , Ecossistema
17.
PLoS Pathog ; 17(4): e1009502, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33826673

RESUMO

Trypanosoma cruzi is the etiologic agent of Chagas' disease. Infected cells with T. cruzi activate several responses that promote unbalance of reactive oxygen species (ROS) that may cause DNA damage that activate cellular responses including DNA repair processes. In this work, HeLa cells and AC16 human cardiomyocyte cell line were infected with T. cruzi to investigate host cell responses at genome level during parasites intracellular life cycle. In fact, alkaline sensitive sites and oxidized DNA bases were detected in the host cell genetic material particularly in early stages of infection. These DNA lesions were accompanied by phosphorylation of the histone H2Ax, inducing γH2Ax, a marker of genotoxic stress. Moreover, Poly [ADP-ribose] polymerase-1 (PARP1) and 8-oxoguanine glycosylase (OGG1) are recruited to host cell nuclei, indicating activation of the DNA repair process. In infected cells, chromatin-associated proteins are carbonylated, as a possible consequence of oxidative stress and the nuclear factor erythroid 2-related factor 2 (NRF2) is induced early after infection, suggesting that the host cell antioxidant defenses are activated. However, at late stages of infection, NRF2 is downregulated. Interestingly, host cells treated with glutathione precursor, N-acetyl cysteine, NRF2 activator (Sulforaphane), and also Benznidonazol (BNZ) reduce parasite burst significantly, and DNA damage. These data indicate that the balance of oxidative stress and DNA damage induction in host cells may play a role during the process of infection itself, and interference in these processes may hamper T. cruzi infection, revealing potential target pathways for the therapy support.


Assuntos
Doença de Chagas/parasitologia , Dano ao DNA , Interações Hospedeiro-Parasita , Estresse Oxidativo , Trypanosoma cruzi/fisiologia , Antioxidantes/metabolismo , Morte Celular , Linhagem Celular , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , Regulação para Baixo , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/patogenicidade
18.
mBio ; 12(2)2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824204

RESUMO

Pyruvate is the final metabolite of glycolysis and can be converted into acetyl coenzyme A (acetyl-CoA) in mitochondria, where it is used as the substrate for the tricarboxylic acid cycle. Pyruvate availability in mitochondria depends on its active transport through the heterocomplex formed by the mitochondrial pyruvate carriers 1 and 2 (MPC1/MPC2). We report here studies on MPC1/MPC2 of Trypanosoma cruzi, the etiologic agent of Chagas disease. Endogenous tagging of T. cruzi MPC1 (TcMPC1) and TcMPC2 with 3×c-Myc showed that both encoded proteins colocalize with MitoTracker to the mitochondria of epimastigotes. Individual knockout (KO) of TcMPC1 and TcMPC2 genes using CRISPR/Cas9 was confirmed by PCR and Southern blot analyses. Digitonin-permeabilized TcMPC1-KO and TcMPC2-KO epimastigotes showed reduced O2 consumption rates when pyruvate, but not succinate, was used as the mitochondrial substrate, while α-ketoglutarate increased their O2 consumption rates due to an increase in α-ketoglutarate dehydrogenase activity. Defective mitochondrial pyruvate import resulted in decreased Ca2+ uptake. The inhibitors UK5099 and malonate impaired pyruvate-driven oxygen consumption in permeabilized control cells. Inhibition of succinate dehydrogenase by malonate indicated that pyruvate needs to be converted into succinate to increase respiration. TcMPC1-KO and TcMPC2-KO epimastigotes showed little growth differences in standard or low-glucose culture medium. However, the ability of trypomastigotes to infect tissue culture cells and replicate as intracellular amastigotes was decreased in TcMPC-KOs. Overall, T. cruzi MPC1 and MPC2 are essential for cellular respiration in the presence of pyruvate, invasion of host cells, and replication of amastigotes.IMPORTANCE Trypanosoma cruzi is the causative agent of Chagas disease. Pyruvate is the end product of glycolysis, and its transport into the mitochondrion is mediated by the mitochondrial pyruvate carrier (MPC) subunits. Using the CRISPR/Cas9 technique, we generated individual T. cruzi MPC1 (TcMPC1) and TcMPC2 knockouts and demonstrated that they are essential for pyruvate-driven respiration. Interestingly, although glycolysis was reported as not an important source of energy for the infective stages, MPC was essential for normal host cell invasion and intracellular replication.


Assuntos
Proteínas de Transporte de Ânions/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Protozoários/genética , Ácido Pirúvico/metabolismo , Trypanosoma cruzi/genética , Trypanosoma cruzi/metabolismo , Proteínas de Transporte de Ânions/metabolismo , Transporte Biológico , Sistemas CRISPR-Cas , Replicação do DNA , Técnicas de Inativação de Genes , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/patogenicidade
19.
Biomedica ; 41(1): 179-186, 2021 03 19.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33761201

RESUMO

Introduction: Belminus ferroae is a triatominae with entomophagous behavior. However, it may occasionally feed on vertebrates. Currently, there is no evidence of natural infection with Trypanosoma cruzi or the occurrence of metacyclogenesis in this species. Objective: To test T. cruzi metacyclogenesis in B. ferroae and the infectivity of their feces or intestinal contents in rodents under laboratory conditions. Materials and methods: Twenty nymphs of B. ferroae were infected with an autochthonous strain of T. cruzi (M/HOM/VE/09/P6). Fecal and urine samples were collected from spontaneous droppings or by compressing the bugs' abdomens and, eventually, by removing their gut contents, and then examined at 10, 20, 30, 40, 50, and 60 days. We quantified T. cruzi parasitic load, as well as the evolutionary forms in feces, urine, and intestinal contents by Giemsa staining. Similarly, we evaluated the infectivity of T. cruzi metacyclic trypomastigotes in albino mice. Results: The parasitological analysis showed three insects (15%) infected with T. cruzi at 30 (n=1), 40 (n=1), and 50 (n=1) days post-infection. We observed parasitic loads of up to 1.62 x 105 trypanosomes/mm3 and metacyclogenesis percentages between 3.5% and 6.78%. Conclusions: This is the first time that T. cruzi metacyclogenesis is reported in a species of the genus Belminus under laboratory conditions and the infectivity of Belminus' feces is demonstrated on a vertebrate host.


Introducción. Belminus ferroae es un triatomino de comportamiento entomófago, sin embargo, puede alimentarse de vertebrados ocasionalmente. No se ha demostrado infección natural por Trypanosoma cruzi en esta especie, como tampoco la metaciclogénesis del parásito. Objetivo. Examinar la metaciclogénesis de T. cruzi en B. ferroae y la capacidad infectiva de las heces o sus contenidos intestinales en roedores. Materiales y métodos. Se analizaron las heces y la orina expulsadas espontáneamente por los insectos o mediante compresión abdominal o extracción del contenido intestinal a los 10, 20, 30, 40, 50 y 60 días. Se cuantificó la carga parasitaria de T. cruzi y sus formas evolutivas se identificaron con tinción de Giemsa. Asimismo, se evaluó en ratones albinos la apacidad infectiva de los tripomastigotes metacíclicos de T. cruzi obtenidos de las heces o contenidos intestinales de los especímenes infectados. Resultados. El análisis parasitológico reveló tres (15 %) insectos infectados con T. cruzi a los 30 (n=1), 40 (n=1) y 50 (n=1) días después de la infección con cargas parasitarias de hasta 1,62 x 105 tripanosomas/mm3 y porcentajes de metaciclogénesis entre el 3,5 y el 6,78 %. Conclusiones. Se demuestra por primera vez, en una especie del género Belminus, la metaciclogenésis de T. cruzi en condiciones de laboratorio y la capacidad infectiva de las heces para un huésped vertebrado.


Assuntos
Fezes/parasitologia , Triatominae/parasitologia , Trypanosoma cruzi/fisiologia , Trypanosoma cruzi/patogenicidade , Animais , Laboratórios , Masculino , Camundongos
20.
Am J Trop Med Hyg ; 104(5): 1631-1638, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33684063

RESUMO

Transmission of Chagas disease (CD) has decreased in recent decades, but the disease remains an important problem in endemic areas. There was an increase in the proportion of nonvector transmission, mainly in non-endemic countries. The aim of this study was to gather evidence concerning healthcare professional's knowledge about CD. Searches were performed through Medline/PubMed, Lilacs, Web of Science databases, and Scielo archives, from which 13/97 articles were selected for a qualitative analysis after full-text reading. Most of the studies were from the United States, the oldest published in 2007 and the most recent in 2020, and most of them used surveys as the evaluation method. Each article used different methods, according to the epidemiological status of vector transmission. Two studies targeted specialty-related questions, and two used focus groups as methods for data gathering. Despite differences between the studies, all of them presented knowledge deficits among healthcare workers, regarding at least one of the evaluated aspects. In comparison with population surveys, healthcare professionals demonstrated higher results related to clinical aspects and awareness of the disease's importance. Most of the articles showed a low perception of CD's knowledge by the participants and a low probability of considering CD in the diagnosis of their patients. A previous contact with the subject was pointed by some studies as capable of improving knowledge of the participants. This study emphasizes the importance of continuing education to address deficits of healthcare professionals' knowledge.


Assuntos
Doença de Chagas/diagnóstico , Doença de Chagas/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/educação , Insetos Vetores/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Brasil/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Educação Continuada/organização & administração , Grupos Focais , Humanos , México/epidemiologia , Espanha/epidemiologia , Inquéritos e Questionários/estatística & dados numéricos , Trypanosoma cruzi/fisiologia , Estados Unidos/epidemiologia
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