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1.
Curr Protoc ; 4(5): e1043, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38706422

RESUMO

Trypanosoma brucei (Tb) is the causative agent of human African trypanosomiasis (HAT), also known as sleeping sickness, which can be fatal if left untreated. An understanding of the parasite's cellular metabolism is vital for the discovery of new antitrypanosomal drugs and for disease eradication. Metabolomics can be used to analyze numerous metabolic pathways described as essential to Tb. brucei but has some limitations linked to the metabolites' physicochemical properties and the extraction process. To develop an optimized method for extracting and analyzing Tb. brucei metabolites, we tested the three most commonly used extraction methods, analyzed the extracts by hydrophilic interaction liquid chromatography high-resolution mass spectrometry (HILIC LC-HRMS), and further evaluated the results using quantitative criteria including the number, intensity, reproducibility, and variability of features, as well as qualitative criteria such as the specific coverage of relevant metabolites. Here, we present the resulting protocols for untargeted metabolomic analysis of Tb. brucei using (HILIC LC-HRMS). © 2024 Wiley Periodicals LLC. Basic Protocol 1: Culture of Trypanosoma brucei brucei parasites Basic Protocol 2: Preparation of samples for metabolomic analysis of Trypanosoma brucei brucei Basic Protocol 3: LC-HRMS-based metabolomic data analysis of Trypanosoma brucei brucei.


Assuntos
Metabolômica , Trypanosoma brucei brucei , Trypanosoma brucei brucei/metabolismo , Metabolômica/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Tripanossomíase Africana/parasitologia
3.
PLoS Negl Trop Dis ; 18(5): e0011516, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38701067

RESUMO

BACKGROUND: Sleeping sickness caused by Trypanosoma brucei rhodesiense is a fatal disease and endemic in Southern and Eastern Africa. There is an urgent need to develop novel diagnostic and control tools to achieve elimination of rhodesiense sleeping sickness which might be achieved through a better understanding of trypanosome gene expression and genetics using endemic isolates. Here, we describe transcriptome profiles and population structure of endemic T. b. rhodesiense isolates in human blood in Malawi. METHODOLOGY: Blood samples of r-HAT cases from Nkhotakota and Rumphi foci were collected in PaxGene tubes for RNA extraction before initiation of r-HAT treatment. 100 million reads were obtained per sample, reads were initially mapped to the human genome reference GRCh38 using HiSat2 and then the unmapped reads were mapped against Trypanosoma brucei reference transcriptome (TriTrypDB54_TbruceiTREU927) using HiSat2. Differential gene expression analysis was done using the DeSeq2 package in R. SNP calling from reads that were mapped to the T. brucei genome was done using GATK in order to identify T.b. rhodesiense population structure. RESULTS: 24 samples were collected from r-HAT cases of which 8 were from Rumphi and 16 from Nkhotakota foci. The isolates from Nkhotakota were enriched with transcripts for cell cycle arrest and stumpy form markers, whereas isolates in Rumphi focus were enriched with transcripts for folate biosynthesis and antigenic variation pathways. These parasite focus-specific transcriptome profiles are consistent with the more virulent disease observed in Rumphi and a less symptomatic disease in Nkhotakota associated with the non-dividing stumpy form. Interestingly, the Malawi T.b. rhodesiense isolates expressed genes enriched for reduced cell proliferation compared to the Uganda T.b. rhodesiense isolates. PCA analysis using SNPs called from the RNAseq data showed that T. b. rhodesiense parasites from Nkhotakota are genetically distinct from those collected in Rumphi. CONCLUSION: Our results suggest that the differences in disease presentation in the two foci is mainly driven by genetic differences in the parasites in the two major endemic foci of Rumphi and Nkhotakota rather than differences in the environment or host response.


Assuntos
Transcriptoma , Trypanosoma brucei rhodesiense , Tripanossomíase Africana , Malaui , Humanos , Trypanosoma brucei rhodesiense/genética , Tripanossomíase Africana/parasitologia , Perfilação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Masculino
4.
Bioorg Med Chem ; 107: 117751, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38762979

RESUMO

In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated IC50s in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Animais , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomicidas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Relação Estrutura-Atividade , Camundongos , Humanos , Administração Oral , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Simulação de Acoplamento Molecular , Tubulina (Proteína)/metabolismo , Testes de Sensibilidade Parasitária , Relação Dose-Resposta a Droga , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Tripanossomíase Africana/tratamento farmacológico
5.
Am J Trop Med Hyg ; 110(6): 1127-1136, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38697074

RESUMO

Animal African trypanosomiasis, also known as nagana, is caused by Trypanosoma species, which cause significant clinical diseases and lead to losses in animal production. We carried out a cross-sectional survey to investigate the composition of vectors and parasite diversity in two districts in the eastern region of Ghana where pigs and cattle were exposed to tsetse bites. We performed cytochrome c oxidase subunit 1 polymerase chain reaction (PCR) to identify tsetse species and internal transcribed spacer 1 PCR to identify Trypanosoma species. Also, we investigated the source of tsetse blood meal based on mitochondrial cytochrome b gene sequence analysis. A total of 229 tsetse, 65 pigs, and 20 cattle were investigated for trypanosomes. An overall vector density of 4.3 tsetse/trap/day was observed. A trypanosome prevalence of 58.9% (95% CI = 52.5-65.1%), 46.2% (95% CI = 34.6-58.1%), and 0.0% (95% CI = 0.0-16.1%) in tsetse, pigs, and cattle, respectively, was detected. Trypanosoma congolense was predominant, with a prevalence of 33.3% (95% CI = 73.3-86.5%) in tsetse. There was evidence of multiple infections in tsetse and pigs. Approximately 39% of the tsetse were positive for multiple infections of T. congolense and Trypanosoma simiae. Parasite prevalence in pigs across the communities was high, with significant differences associated between locations (χ2 = 28.06, 95% CI = 0.05-0.81, P = 0.0009). Tsetse blood meal analysis revealed feeding on domestic Sus scrofa domesticus (pigs) and Phacochoerus africanus (warthogs). Infective tsetse may transmit trypanosomes to livestock and humans in the communities studied.


Assuntos
Trypanosoma , Tripanossomíase Africana , Moscas Tsé-Tsé , Animais , Gana/epidemiologia , Moscas Tsé-Tsé/parasitologia , Bovinos , Tripanossomíase Africana/transmissão , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária , Suínos , Trypanosoma/isolamento & purificação , Trypanosoma/genética , Trypanosoma/classificação , Estudos Transversais , Doenças dos Suínos/transmissão , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/parasitologia , Insetos Vetores/parasitologia , Florestas , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/transmissão , Doenças dos Bovinos/parasitologia , Prevalência , Feminino
6.
Int Immunopharmacol ; 134: 112250, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38749335

RESUMO

Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8+, CD4+ T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection.


Assuntos
Citocinas , Transdução de Sinais , Receptor Toll-Like 9 , Trypanosoma brucei brucei , Tripanossomíase Africana , Receptor Toll-Like 9/metabolismo , Receptor Toll-Like 9/agonistas , Animais , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Camundongos , Citocinas/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Humanos
7.
Res Vet Sci ; 174: 105290, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38776695

RESUMO

This study reports assessment of the sensitivity of diagnostic techniques to detect T. vivax in experimentally infected cattle. Additionally, it describes T. vivax extravascular parasitism during the acute and chronic phases of trypanosomosis and congenital transmission. The T. vivax diagnosis was compared using blood samples collected from the jugular, coccygeal and ear tip veins. For this study, 13 males and two females were infected with ≈ 1 × 106 viable T. vivax trypomastigotes (D0). One animal was kept as a negative control during the entire study. The 13 infected males were euthanized between 14 and 749 days post-infection (DPI). After confirming the cyclicity of both females (9 months of age), they were naturally mated with a bull. One female was euthanized at 840 DPI, and the other at 924 DPI. The two calves, one from each female, were euthanized at six months of age (924 DPI), and the negative control at 924 DPI. During this period, T. vivax in blood was assessed using direct methods (Woo test, cPCR, microscopic examination of fresh wet blood films and parasite quantification - Brener method), and serological methods (IFAT, ELISA, and IA). Tissue samples were collected from the liver, spleen, brain, cerebellum, heart, testicles, epididymis, kidneys, eyeballs, pre-scapular lymph nodes, ear tips, mammary glands, uterus, and ovaries. The protozoan DNA was examined using LAMP. There was no difference in the detection of T. vivax using the Woo test and Brener method among the jugular, coccygeal, and ear tip veins. The sensitivity of the detection methods varied depending on the disease phase. Direct methods (Woo test, Brener method, and cPCR) demonstrated higher sensitivity during the acute phase, while serological methods (IFAT, ELISA, and IA) were more sensitive during the chronic phase. Anti-T. vivax antibodies were detected up to 924 DPI. Tissue evaluation using LAMP demonstrated the presence of T. vivax DNA and associated histopathological changes up to 840 or 924 DPI. Only in mammary glands and ovaries was no DNA detected. The most frequently observed histopathological alteration was lymphohistioplasmocytic inflammatory infiltrate. No transplacental transmission of T. vivax was observed.


Assuntos
Doenças dos Bovinos , Trypanosoma vivax , Animais , Bovinos , Feminino , Masculino , Doenças dos Bovinos/transmissão , Doenças dos Bovinos/parasitologia , Doenças dos Bovinos/sangue , Doenças dos Bovinos/diagnóstico , Transmissão Vertical de Doenças Infecciosas/veterinária , Tripanossomíase Africana/veterinária , Tripanossomíase Africana/transmissão , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/sangue
8.
Parasit Vectors ; 17(1): 215, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734633

RESUMO

BACKGROUND: Animal African trypanosomiasis, which is caused by different species of African trypanosomes, is a deadly disease in livestock. Although African trypanosomes are often described as blood-borne parasites, there have been recent reappraisals of the ability of these parasites to reside in a wide range of tissues. However, the majority of those studies were conducted on non-natural hosts infected with only one species of trypanosome, and it is unclear whether a similar phenomenon occurs during natural animal infections, where multiple species of these parasites may be present. METHODS: The infective trypanosome species in the blood and other tissues (adipose and skin) of a natural host (cows, goats and sheep) were determined using a polymerase chain reaction-based diagnostic. RESULTS: The animals were found to harbour multiple species of trypanosomes. Different patterns of distribution were observed within the host tissues; for instance, in some animals, the blood was positive for the DNA of one species of trypanosome and the skin and adipose were positive for the DNA of another species. Moreover, the rate of detection of trypanosome DNA was highest for skin adipose and lowest for the blood. CONCLUSIONS: The findings reported here emphasise the complexity of trypanosome infections in a natural setting, and may indicate different tissue tropisms between the different parasite species. The results also highlight the need to include adipose and skin tissues in future diagnostic and treatment strategies.


Assuntos
Tecido Adiposo , Doenças das Cabras , Cabras , Pele , Trypanosoma , Tripanossomíase Africana , Animais , Cabras/parasitologia , Tripanossomíase Africana/veterinária , Tripanossomíase Africana/parasitologia , Tecido Adiposo/parasitologia , Trypanosoma/genética , Trypanosoma/isolamento & purificação , Trypanosoma/classificação , Pele/parasitologia , Ovinos/parasitologia , Doenças das Cabras/parasitologia , Bovinos , Reação em Cadeia da Polimerase , Doenças dos Ovinos/parasitologia , DNA de Protozoário/genética , Doenças dos Bovinos/parasitologia
10.
Clin Infect Dis ; 78(Supplement_2): S175-S182, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38662705

RESUMO

BACKGROUND: Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals. METHODS: We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases. RESULTS: We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission. CONCLUSIONS: Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease.


Assuntos
Infecções Assintomáticas , Doença de Chagas , Leishmaniose Visceral , Modelos Teóricos , Doenças Negligenciadas , Humanos , Doenças Negligenciadas/prevenção & controle , Doenças Negligenciadas/epidemiologia , Doença de Chagas/transmissão , Doença de Chagas/prevenção & controle , Doença de Chagas/epidemiologia , Doença de Chagas/tratamento farmacológico , Infecções Assintomáticas/epidemiologia , Leishmaniose Visceral/prevenção & controle , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/transmissão , Leishmaniose Visceral/tratamento farmacológico , Tripanossomíase Africana/prevenção & controle , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/transmissão , Tripanossomíase Africana/tratamento farmacológico , Índia/epidemiologia , Animais
11.
PLoS Comput Biol ; 20(4): e1011993, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38557869

RESUMO

The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.


Assuntos
Tripanossomíase Africana , Animais , Humanos , Tripanossomíase Africana/epidemiologia , República Democrática do Congo/epidemiologia , Modelos Teóricos , Previsões , Cadeias de Markov , Trypanosoma brucei gambiense
12.
PLoS Negl Trop Dis ; 18(4): e0011578, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38626189

RESUMO

BACKGROUND: The insecticide-treated baits known as Tiny Targets are one of the cheapest means of controlling riverine species of tsetse flies, the vectors of the trypanosomes that cause sleeping sickness in humans. Models of the efficacy of these targets deployed near rivers are potentially useful in planning control campaigns and highlighting the principles involved. METHODS AND PRINCIPAL FINDINGS: To evaluate the potential of models, we produced a simple non-seasonal model of the births, deaths, mobility and aging of tsetse, and we programmed it to simulate the impact of seven years of target use against the tsetse, Glossina fuscipes fuscipes, in the riverine habitats of NW Uganda. Particular attention was given to demonstrating that the model could explain three matters of interest: (i) good control can be achieved despite the degradation of targets, (ii) local elimination of tsetse is impossible if invasion sources are not tackled, and (iii) with invasion and target degradation it is difficult to detect any effect of control on the age structure of the tsetse population. CONCLUSIONS: Despite its simplifications, the model can assist planning and teaching, but allowance should be made for any complications due to seasonality and management challenges associated with greater scale.


Assuntos
Controle de Insetos , Inseticidas , Moscas Tsé-Tsé , Moscas Tsé-Tsé/fisiologia , Moscas Tsé-Tsé/parasitologia , Animais , Controle de Insetos/métodos , Uganda , Inseticidas/farmacologia , Humanos , Tripanossomíase Africana/prevenção & controle , Tripanossomíase Africana/epidemiologia , Insetos Vetores/parasitologia , Insetos Vetores/fisiologia
13.
Int J Mol Sci ; 25(8)2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38673995

RESUMO

In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of Trypanosoma brucei rhodesiense and Plasmodium falciparum, are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively. Therefore, in our study we identified a novel lead-like compound, i.e., inhibitor 2b, which we proved to be active against both targets, with a Ki = 5.06 µM towards rhodesain and an IC50 = 40.43 µM against falcipain-2.


Assuntos
Inibidores de Cisteína Proteinase , Nitrilas , Plasmodium falciparum , Trypanosoma brucei rhodesiense , Tripanossomíase Africana , Humanos , Antimaláricos/uso terapêutico , Antimaláricos/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Inibidores de Cisteína Proteinase/química , Malária/tratamento farmacológico , Nitrilas/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico
14.
PLoS Negl Trop Dis ; 18(4): e0012111, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38626188

RESUMO

BACKGROUND: Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the 20th century. Sustained, coordinated efforts by different stakeholders working with national sleeping sickness control programmes (NSSCPs) succeeded in controlling the disease and reducing the number of cases to historically low levels. In 2012, WHO targeted the elimination of the disease as a public health problem by 2020. This goal has been reached and a new ambitious target was stated in the WHO road map for NTDs 2021-2030 and endorsed by the 73rd World Health Assembly: the elimination of gambiense HAT transmission (i.e. reducing the number of reported cases to zero). The interruption of transmission was not considered as an achievable goal for rhodesiense HAT, as it would require vast veterinary interventions rather than actions at the public health level. METHODOLOGY/PRINCIPAL FINDINGS: Data reported to WHO by NSSCPs were harmonized, verified, georeferenced and included in the atlas of HAT. A total of 802 cases were reported in 2021 and 837 in 2022. This is below the target for elimination as a public health problem at the global level (< 2000 HAT cases/year); 94% of the cases were caused by infection with T. b. gambiense. The areas reporting ≥ 1 HAT case/10 000 inhabitants/year in 2018-2022 cover a surface of 73 134 km2, with only 3013 km2 at very high or high risk. This represents a reduction of 90% from the baseline figure for 2000-2004, the target set for the elimination of HAT as a public health problem. For the surveillance of the disease, 4.5 million people were screened for gambiense HAT with serological tests in 2021-2022, 3.6 million through active screening and 0.9 million by passive screening. In 2021 and 2022 the elimination of HAT as a public health problem was validated in Benin, Uganda, Equatorial Guinea and Ghana for gambiense HAT and in Rwanda for rhodesiense HAT. To reach the next goal of elimination of transmission of gambiense HAT, countries have to report zero cases of human infection with T. b. gambiense for a period of at least 5 consecutive years. The criteria and procedures to verify elimination of transmission have been recently published by WHO. CONCLUSIONS/SIGNIFICANCE: HAT elimination as a public health problem has been reached at global level, with seven countries already validated as having reached this goal. This achievement was made possible by the work of NSSCPs, supported by different public and private partners, and coordinated by WHO. The new challenging goal now is to reach zero cases by 2030. To reach this goal is crucial to maintain the engagement and support of donors and stakeholders and to keep the involvement and coordination of all partners. Along with the focus on elimination of transmission of gambiense HAT, it is important not to neglect rhodesiense HAT, which is targeted for elimination as a public health problem in the WHO road map for NTDs 2021-2030.


Assuntos
Erradicação de Doenças , Tripanossomíase Africana , Organização Mundial da Saúde , Tripanossomíase Africana/prevenção & controle , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/transmissão , Humanos , Trypanosoma brucei gambiense , África Subsaariana/epidemiologia , Doenças Negligenciadas/prevenção & controle , Doenças Negligenciadas/epidemiologia , Animais , Monitoramento Epidemiológico
15.
PLoS Negl Trop Dis ; 18(4): e0012103, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38620045

RESUMO

BACKGROUND: The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB. METHODOLOGY: Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB. RESULTS: Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite. CONCLUSION: Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.


Assuntos
Ginkgo biloba , Melarsoprol , Estresse Oxidativo , Extratos Vegetais , Trypanosoma brucei rhodesiense , Tripanossomíase Africana , Animais , Camundongos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ginkgo biloba/química , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Melarsoprol/farmacologia , Masculino , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Encéfalo/efeitos dos fármacos , Encéfalo/parasitologia , Encéfalo/metabolismo , Encéfalo/patologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico
17.
Molecules ; 29(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38611890

RESUMO

Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for free. Aiming to validate herbal remedies in use, we selected nine medicinal plants and assessed their antitrypanosomal activity. A total of 122 extracts were prepared using different plant parts and solvents. A total of 15 extracts from seven different plants exhibited in vitro activity (>70% at 20 µg/mL) against Trypanosoma brucei rhodesiense bloodstream forms. The dichloromethane extract of Nymphaea lotus (leaves and leaflets) and the ethanolic extract of Brasenia schreberi (leaves) had IC50 values ≤ 10 µg/mL. These two aquatic plants are of particular interest. They are being co-applied in the form of a decoction of leaves because they are considered by local healers as male and female of the same species, the ethnotaxon "longa dia simbi". Bioassay-guided fractionation led to the identification of eight active molecules: gallic acid (IC50 0.5 µg/mL), methyl gallate (IC50 1.1 µg/mL), 2,3,4,6-tetragalloyl-glucopyranoside, ethyl gallate (IC50 0.5 µg/mL), 1,2,3,4,6-pentagalloyl-ß-glucopyranoside (IC50 20 µg/mL), gossypetin-7-O-ß-glucopyranoside (IC50 5.5 µg/mL), and hypolaetin-7-O-glucoside (IC50 5.7 µg/mL) in B. schreberi, and 5-[(8Z,11Z,14Z)-heptadeca-8,11,14-trienyl] resorcinol (IC50 5.3 µg/mL) not described to date in N. lotus. Five of these active constituents were detected in the traditional preparation. This work provides the first evidence for the ethnomedicinal use of these plants in the management of sleeping sickness in Angola.


Assuntos
Antiprotozoários , Nymphaea , Tripanossomíase Africana , Humanos , Animais , Angola , Sementes , Antiprotozoários/farmacologia , Extratos Vegetais/farmacologia
18.
PLoS Pathog ; 20(4): e1012186, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38648216

RESUMO

In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role is fulfilled by a dense, glycosylated protein layer composed of variant surface glycoproteins (VSGs), which undergo antigenic variation and provide a physical barrier that shields the underlying invariant surface glycoproteins (ISGs). The protective shield's limited permeability comes at the cost of restricted access to the extracellular host environment, raising questions regarding the specific function of the ISG repertoire. In this study, we employ an integrative structural biology approach to show that intrinsically disordered membrane-proximal regions are a common feature of members of the ISG super-family, conferring the ability to switch between compact and elongated conformers. While the folded, membrane-distal ectodomain is buried within the VSG layer for compact conformers, their elongated counterparts would enable the extension beyond it. This dynamic behavior enables ISGs to maintain a low immunogenic footprint while still allowing them to engage with the host environment when necessary. Our findings add further evidence to a dynamic molecular organization of trypanosome surface antigens wherein intrinsic disorder underpins the characteristics of a highly flexible ISG proteome to circumvent the constraints imposed by the VSG coat.


Assuntos
Tripanossomíase Africana , Glicoproteínas Variantes de Superfície de Trypanosoma , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/imunologia , Proteínas de Protozoários/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Animais
19.
PLoS Pathog ; 20(4): e1012166, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38635823

RESUMO

Trypanosoma brucei are protozoan parasites that cause sleeping sickness in humans and nagana in cattle. Inside the mammalian host, a quorum sensing-like mechanism coordinates its differentiation from a slender replicative form into a quiescent stumpy form, limiting growth and activating metabolic pathways that are beneficial to the parasite in the insect host. The post-translational modification of proteins with the Small Ubiquitin-like MOdifier (SUMO) enables dynamic regulation of cellular metabolism. SUMO can be conjugated to its targets as a monomer but can also form oligomeric chains. Here, we have investigated the role of SUMO chains in T. brucei by abolishing the ability of SUMO to polymerize. We have found that parasites able to conjugate only SUMO monomers are primed for differentiation. This was demonstrated for monomorphic lines that are normally unable to produce stumpy forms in response to quorum sensing signaling in mice, and also for pleomorphic cell lines in which stumpy cells were observed at unusually low parasitemia levels. SUMO chain mutants showed a stumpy compatible transcriptional profile and better competence to differentiate into procyclics. Our study indicates that SUMO depolymerization may represent a coordinated signal triggered during stumpy activation program.


Assuntos
Trypanosoma brucei brucei , Animais , Trypanosoma brucei brucei/metabolismo , Camundongos , Tripanossomíase Africana/parasitologia , Diferenciação Celular , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Processamento de Proteína Pós-Traducional , Percepção de Quorum/fisiologia , Humanos , Sumoilação
20.
Res Vet Sci ; 171: 105227, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38513458

RESUMO

African animal trypanosomosis is a parasitic disease that causes significant economic losses in livestock due to anaemia, loss of condition, emaciation, and mortality. It is a key impediment to increased cattle output and productivity in Ethiopia. Cross-sectional entomological and parasitological studies were performed in the Gambella Region state of southwestern Ethiopia to estimate the prevalence of bovine trypanosomosis, apparent fly density, and potential risk factors. Blood samples were taken from 546 cattle for the parasitological study and analyzed using the buffy coat technique and stained with Giemsa. A total of 189 biconical (89) and NGU (100) traps were deployed in the specified districts for the entomological survey. The overall prevalence of trypanosomosis at the animal level was 5.5% (95% CI: 3.86-7.75). Trypanosoma vivax (50.0%), T. congolense (30.0%), T. brucei (20.0%), and no mixed trypanosome species were found. The prevalence of trypanosomosis was significantly (p < 0.05) affected by altitude, body score conditions, age, mean packed cell volume (PCV), and peasant associations, while sex and coat color had no significant effect. According to the entomological survey results, a total of 2303 flies were captured and identified as tsetse (Glossina pallidipes (5.3%)) and G. fuscipes fuscipes (3.3%) and other biting flies (Tabanus (60.1%) and Stomoxys (31.3%)). In the current study, the overall apparent density was 4.1 flies/trap/day. This study shows that trypanosomosis remains a significant cattle disease in the Gambella regional state even during the dry season. Thus, the findings support the necessity to improve vector and parasite control measures in the area.


Assuntos
Doenças dos Bovinos , Tripanossomíase Africana , Tripanossomíase Bovina , Tripanossomíase , Moscas Tsé-Tsé , Bovinos , Animais , Estudos Transversais , Etiópia/epidemiologia , Moscas Tsé-Tsé/parasitologia , Insetos Vetores , Tripanossomíase Bovina/epidemiologia , Tripanossomíase Bovina/parasitologia , Tripanossomíase/veterinária , Prevalência , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária , Doenças dos Bovinos/epidemiologia
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