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1.
Nat Commun ; 12(1): 1052, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594070

RESUMO

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.


Assuntos
Glicólise/efeitos dos fármacos , Fosfofrutoquinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Trypanosoma/enzimologia , Tripanossomíase Africana/metabolismo , Tripanossomíase Africana/parasitologia , Doença Aguda , Regulação Alostérica/efeitos dos fármacos , Animais , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estimativa de Kaplan-Meier , Camundongos , Parasitos/efeitos dos fármacos , Fosfofrutoquinases/química , Fosfofrutoquinases/metabolismo , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Multimerização Proteica , Relação Estrutura-Atividade , Trypanosoma/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico
2.
PLoS Negl Trop Dis ; 15(1): e0008267, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33406097

RESUMO

African trypanosomiasis (AT) is a neglected disease of both humans and animals caused by Trypanosoma parasites, which are transmitted by obligate hematophagous tsetse flies (Glossina spp.). Knowledge on tsetse fly vertebrate hosts and the influence of tsetse endosymbionts on trypanosome presence, especially in wildlife-human-livestock interfaces, is limited. We identified tsetse species, their blood-meal sources, and correlations between endosymbionts and trypanosome presence in tsetse flies from the trypanosome-endemic Maasai Mara National Reserve (MMNR) in Kenya. Among 1167 tsetse flies (1136 Glossina pallidipes, 31 Glossina swynnertoni) collected from 10 sampling sites, 28 (2.4%) were positive by PCR for trypanosome DNA, most (17/28) being of Trypanosoma vivax species. Blood-meal analyses based on high-resolution melting analysis of vertebrate cytochrome c oxidase 1 and cytochrome b gene PCR products (n = 354) identified humans as the most common vertebrate host (37%), followed by hippopotamus (29.1%), African buffalo (26.3%), elephant (3.39%), and giraffe (0.84%). Flies positive for trypanosome DNA had fed on hippopotamus and buffalo. Tsetse flies were more likely to be positive for trypanosomes if they had the Sodalis glossinidius endosymbiont (P = 0.0002). These findings point to complex interactions of tsetse flies with trypanosomes, endosymbionts, and diverse vertebrate hosts in wildlife ecosystems such as in the MMNR, which should be considered in control programs. These interactions may contribute to the maintenance of tsetse populations and/or persistent circulation of African trypanosomes. Although the African buffalo is a key reservoir of AT, the higher proportion of hippopotamus blood-meals in flies with trypanosome DNA indicates that other wildlife species may be important in AT transmission. No trypanosomes associated with human disease were identified, but the high proportion of human blood-meals identified are indicative of human African trypanosomiasis risk. Our results add to existing data suggesting that Sodalis endosymbionts are associated with increased trypanosome presence in tsetse flies.


Assuntos
Animais Selvagens/parasitologia , Insetos Vetores/parasitologia , Gado/parasitologia , Simbiose/fisiologia , Trypanosoma/fisiologia , Moscas Tsé-Tsé/parasitologia , Animais , Artiodáctilos/parasitologia , Sangue , Búfalos/parasitologia , Ecossistema , Elefantes/parasitologia , Enterobacteriaceae , Humanos , Quênia , Reação em Cadeia da Polimerase , Trypanosoma/genética , Trypanosoma vivax , Tripanossomíase Africana/parasitologia
3.
PLoS Pathog ; 17(1): e1009224, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481935

RESUMO

Animal African trypanosomiasis (AAT) is a severe, wasting disease of domestic livestock and diverse wildlife species. The disease in cattle kills millions of animals each year and inflicts a major economic cost on agriculture in sub-Saharan Africa. Cattle AAT is caused predominantly by the protozoan parasites Trypanosoma congolense and T. vivax, but laboratory research on the pathogenic stages of these organisms is severely inhibited by difficulties in making even minor genetic modifications. As a result, many of the important basic questions about the biology of these parasites cannot be addressed. Here we demonstrate that an in vitro culture of the T. congolense genomic reference strain can be modified directly in the bloodstream form reliably and at high efficiency. We describe a parental single marker line that expresses T. congolense-optimized T7 RNA polymerase and Tet repressor and show that minichromosome loci can be used as sites for stable, regulatable transgene expression with low background in non-induced cells. Using these tools, we describe organism-specific constructs for inducible RNA-interference (RNAi) and demonstrate knockdown of multiple essential and non-essential genes. We also show that a minichromosomal site can be exploited to create a stable bloodstream-form line that robustly provides >40,000 independent stable clones per transfection-enabling the production of high-complexity libraries of genome-scale. Finally, we show that modified forms of T. congolense are still infectious, create stable high-bioluminescence lines that can be used in models of AAT, and follow the course of infections in mice by in vivo imaging. These experiments establish a base set of tools to change T. congolense from a technically challenging organism to a routine model for functional genetics and allow us to begin to address some of the fundamental questions about the biology of this important parasite.


Assuntos
Genética Microbiana , Proteínas de Protozoários/genética , Transgenes , Trypanosoma congolense/genética , Trypanosoma congolense/patogenicidade , Tripanossomíase Africana/parasitologia , Animais , Feminino , Genoma de Protozoário , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tripanossomíase Africana/genética
4.
Nat Microbiol ; 6(3): 392-400, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33462435

RESUMO

Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly 100 yr. Recent studies revealed that trypanosome strains that express the variant surface glycoprotein (VSG) VSGsur possess heightened resistance to suramin. Here, we show that VSGsur binds tightly to suramin but other VSGs do not. By solving high-resolution crystal structures of VSGsur and VSG13, we also demonstrate that these VSGs define a structurally divergent subgroup of the coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.


Assuntos
Resistência a Medicamentos/imunologia , Suramina/metabolismo , Trypanosoma brucei rhodesiense/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/química , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo , Variação Antigênica/efeitos dos fármacos , Variação Antigênica/imunologia , Sítios de Ligação , Cristalografia por Raios X , Resistência a Medicamentos/genética , Endocitose/genética , Evasão da Resposta Imune , Mutação , Ligação Proteica , Conformação Proteica , Suramina/toxicidade , Tripanossomicidas/metabolismo , Tripanossomicidas/toxicidade , Trypanosoma brucei rhodesiense/química , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/metabolismo , Tripanossomíase Africana/parasitologia , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429951

RESUMO

African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host's body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N'Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N'Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.


Assuntos
Imunidade Inata/genética , Trypanosoma/genética , Tripanossomíase Africana/genética , Animais , Bovinos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/imunologia , Fígado/metabolismo , Fígado/parasitologia , Especificidade de Órgãos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Baço/metabolismo , Baço/parasitologia , Trypanosoma/patogenicidade , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissão , Tripanossomíase Africana/veterinária , Moscas Tsé-Tsé/parasitologia , Moscas Tsé-Tsé/patogenicidade
6.
PLoS Comput Biol ; 17(1): e1008532, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513134

RESUMO

Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions. We present a Bayesian fitting methodology, applied to 168 endemic health zones (∼100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework. It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection. Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters. Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s. Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers. The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly-on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu-Equateur and Bandundu having had the highest case burdens in 2000. This analysis also sets out a framework to enable future predictions for the country.


Assuntos
Modelos Estatísticos , Trypanosoma brucei gambiense , Tripanossomíase Africana , Teorema de Bayes , Biologia Computacional , República Democrática do Congo/epidemiologia , Humanos , Modelos Biológicos , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissão
7.
PLoS One ; 15(9): e0232306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986707

RESUMO

Tsetse eradication continues to be a top priority for African governments including that of Senegal, which embarked on a project to eliminate Glossina palpalis gambiensis from the Niayes area, following an area-wide integrated pest management approach with an SIT component. A successful SIT programme requires competitive sterile males of high biological quality. This may be hampered by handling processes including irradiation and the release mechanisms, necessitating continued improvement of these processes, to maintain the quality of flies. A new prototype of an automated chilled adult release system (Bruno Spreader Innovation, (BSI™)) for tsetse flies was tested for its accuracy (in counting) and release rate consistency. Also, its impact on the quality of the released sterile males was evaluated on performance indicators, including flight propensity, mating competitiveness, premating and mating duration, insemination rate of mated females and survival of male flies. The BSITM release system accurately counted and homogenously released flies at the lowest motor speed set (0.6 rpm), at a consistent rate of 60±9.58 males/min. Also, the release process, chilling (6 ± 1°C) and passing of flies through the machine) had no significant negative impact on the male flight propensity, mating competitiveness, premating and mating durations and the insemination rates. Only the survival of flies was negatively affected whether under feeding or starvation. The positive results of this study show that the BSI™ release system is promising for use in future tsetse SIT programmes. However, the negative impact of the release process on survival of flies needs to be addressed in future studies and results of this study confirmed under operational field conditions in West Africa.


Assuntos
Temperatura Baixa/efeitos adversos , Infertilidade Masculina/veterinária , Controle Biológico de Vetores/métodos , Tripanossomíase Africana/prevenção & controle , Moscas Tsé-Tsé/fisiologia , Animais , Vetores de Doenças , Feminino , Voo Animal/fisiologia , Humanos , Infertilidade Masculina/etiologia , Gado/parasitologia , Masculino , Controle Biológico de Vetores/instrumentação , Senegal , Comportamento Sexual Animal/fisiologia , Trypanosoma/patogenicidade , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária , Moscas Tsé-Tsé/parasitologia
8.
PLoS Negl Trop Dis ; 14(9): e0008588, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925917

RESUMO

BACKGROUND: Significant efforts to control human African trypanosomiasis (HAT) over the two past decades have resulted in drastic decrease of its prevalence in Côte d'Ivoire. In this context, passive surveillance, integrated in the national health system and based on clinical suspicion, was reinforced. We describe here the health-seeking pathway of a girl who was the first HAT patient diagnosed through this strategy in August 2017. METHODS: After definitive diagnosis of this patient, epidemiological investigations were carried out into the clinical evolution and the health and therapeutic itinerary of the patient before diagnosis. RESULTS: At the time of diagnosis, the patient was positive in both serological and molecular tests and trypanosomes were detected in blood and cerebrospinal fluid. She suffered from important neurological disorders. The first disease symptoms had appeared three years earlier, and the patient had visited several public and private peripheral health care centres and hospitals in different cities. The failure to diagnose HAT for such a long time caused significant health deterioration and was an important financial burden for the family. CONCLUSION: This description illustrates the complexity of detecting the last HAT cases due to complex diagnosis and the progressive disinterest and unawareness by both health professionals and the population. It confirms the need of implementing passive surveillance in combination with continued sensitization and health staff training.


Assuntos
Diagnóstico Tardio/economia , Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/tratamento farmacológico , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Sangue/parasitologia , Líquido Cefalorraquidiano/parasitologia , Criança , Indicadores de Doenças Crônicas , Costa do Marfim/epidemiologia , Feminino , Humanos , Doenças Negligenciadas/parasitologia , Administração dos Cuidados ao Paciente/economia , Trypanosoma brucei gambiense/isolamento & purificação , Tripanossomíase Africana/parasitologia
9.
PLoS One ; 15(8): e0237187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833981

RESUMO

INTRODUCTION: Infection of equids with Trypanosoma brucei (T. brucei) ssp. is of socioeconomic importance across sub-Saharan Africa as the disease often progresses to cause fatal meningoencephalitis. Loop-mediated isothermal amplification (LAMP) has been developed as a cost-effective molecular diagnostic test and is potentially applicable for use in field-based laboratories. PART I: Threshold levels for T. brucei ssp. detection by LAMP were determined using whole equine blood specimens spiked with known concentrations of parasites. Results were compared to OIE antemortem gold standard of T. brucei-PCR (TBR-PCR). RESULTS I: Threshold for detection of T. brucei ssp. on extracted DNA from whole blood was 1 parasite/ml blood for LAMP and TBR-PCR, and there was excellent agreement (14/15) between tests at high (1 x 103/ml) concentrations of parasites. Detection threshold was 100 parasites/ml using LAMP on whole blood (LWB). Threshold for LWB improved to 10 parasites/ml with detergent included. Performance was excellent for LAMP at high (1 x 103/ml) concentrations of parasites (15/15, 100%) but was variable at lower concentrations. Agreement between tests was weak to moderate, with the highest for TBR-PCR and LAMP on DNA extracted from whole blood (Cohen's kappa 0.95, 95% CI 0.64-1.00). PART II: A prospective cross-sectional study of working equids meeting clinical criteria for trypanosomiasis was undertaken in The Gambia. LAMP was evaluated against subsequent TBR-PCR. RESULTS II: Whole blood samples from 321 equids in The Gambia were processed under field conditions. There was weak agreement between LWB and TBR-PCR (Cohen's kappa 0.34, 95% CI 0.19-0.49) but excellent agreement when testing CSF (100% agreement on 6 samples). CONCLUSIONS: Findings support that LAMP is comparable to PCR when used on CSF samples in the field, an important tool for clinical decision making. Results suggest repeatability is low in animals with low parasitaemia. Negative samples should be interpreted in the context of clinical presentation.


Assuntos
Doenças dos Cavalos/parasitologia , Cavalos/parasitologia , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Reação em Cadeia da Polimerase/métodos , Trypanosoma brucei brucei/genética , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/veterinária , Animais , Estudos Transversais , DNA de Protozoário/sangue , DNA de Protozoário/genética , Feminino , Gâmbia , Masculino , Técnicas de Diagnóstico Molecular/economia , Técnicas de Amplificação de Ácido Nucleico/economia , Reação em Cadeia da Polimerase/economia , Estudos Prospectivos , Sensibilidade e Especificidade , Tripanossomíase Africana/parasitologia
10.
PLoS Negl Trop Dis ; 14(7): e0008458, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644992

RESUMO

Defining mode of action is vital for both developing new drugs and predicting potential resistance mechanisms. Sensitivity of African trypanosomes to pentamidine and melarsoprol is predominantly mediated by aquaglyceroporin 2 (TbAQP2), a channel associated with water/glycerol transport. TbAQP2 is expressed at the flagellar pocket membrane and chimerisation with TbAQP3 renders parasites resistant to both drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; that TbAQP2 mediates pentamidine translocation across the plasma membrane or via binding to TbAQP2, with subsequent endocytosis and presumably transport across the endosomal/lysosomal membrane, but as trafficking and regulation of TbAQPs is uncharacterised this remains unresolved. We demonstrate that TbAQP2 is organised as a high order complex, is ubiquitylated and is transported to the lysosome. Unexpectedly, mutation of potential ubiquitin conjugation sites, i.e. cytoplasmic-oriented lysine residues, reduced folding and tetramerization efficiency and triggered ER retention. Moreover, TbAQP2/TbAQP3 chimerisation, as observed in pentamidine-resistant parasites, also leads to impaired oligomerisation, mislocalisation and increased turnover. These data suggest that TbAQP2 stability is highly sensitive to mutation and that instability contributes towards the emergence of drug resistance.


Assuntos
Aquagliceroporinas/metabolismo , Resistência a Medicamentos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei , Tripanossomíase Africana/parasitologia , Sequência de Aminoácidos , Animais , Aquagliceroporinas/química , Estabilidade Proteica
11.
Int J Mol Sci ; 21(5)2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32121441

RESUMO

Unicellular eukaryotes of the Trypanosomatidae family include human and animal pathogens that belong to the Trypanosoma and Leishmania genera. Diagnosis of the diseases they cause requires the sampling of body fluids (e.g., blood, lymph, peritoneal fluid, cerebrospinal fluid) or organ biopsies (e.g., bone marrow, spleen), which are mostly obtained through invasive methods. Body fluids or appendages can be alternatives to these invasive biopsies but appropriateness remains poorly studied. To further address this question, we perform a systematic review on clues evidencing the presence of parasites, genetic material, antibodies, and antigens in body secretions, appendages, or the organs or proximal tissues that produce these materials. Paper selection was based on searches in PubMed, Web of Science, WorldWideScience, SciELO, Embase, and Google. The information of each selected article (n = 333) was classified into different sections and data were extracted from 77 papers. The presence of Trypanosomatidae parasites has been tracked in most of organs or proximal tissues that produce body secretions or appendages, in naturally or experimentally infected hosts. The meta-analysis highlights the paucity of studies on human African trypanosomiasis and an absence on animal trypanosomiasis. Among the collected data high heterogeneity in terms of the I2 statistic (100%) is recorded. A high positivity is recorded for antibody and genetic material detection in urine of patients and dogs suffering leishmaniasis, and of antigens for leishmaniasis and Chagas disease. Data on conjunctival swabs can be analyzed with molecular methods solely for dogs suffering canine visceral leishmaniasis. Saliva and hair/bristles showed a pretty good positivity that support their potential to be used for leishmaniasis diagnosis. In conclusion, our study pinpoints significant gaps that need to be filled in order to properly address the interest of body secretion and hair or bristles for the diagnosis of infections caused by Leishmania and by other Trypanosomatidae parasites.


Assuntos
Leishmania/isolamento & purificação , Trypanosoma/isolamento & purificação , Trypanosomatina/isolamento & purificação , Animais , Doença de Chagas/diagnóstico , Doença de Chagas/parasitologia , Doenças do Cão/diagnóstico , Doenças do Cão/parasitologia , Cães , Humanos , Leishmania/patogenicidade , Leishmaniose/diagnóstico , Leishmaniose/parasitologia , Trypanosoma/patogenicidade , Trypanosomatina/patogenicidade , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária
12.
Sci Rep ; 10(1): 2824, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071365

RESUMO

The Djallonké (West African Dwarf) sheep is a small-sized haired sheep resulting from a costly evolutionary process of natural adaptation to the harsh environment of West Africa including trypanosome challenge. However, genomic studies carried out in this sheep are scant. In this research, genomic data of 184 Djallonké sheep (and 12 Burkina-Sahel sheep as an outgroup) generated using medium-density SNP Chips were analyzed. Three different statistics (iHS, XP-EHH and nSL) were applied to identify candidate selection sweep regions spanning genes putatively associated with adaptation of sheep to the West African environment. A total of 207 candidate selection sweep regions were defined. Gene-annotation enrichment and functional annotation analyses allowed to identify three statistically significant functional clusters involving 12 candidate genes. Genes included in Functional Clusters associated to selection signatures were mainly related to metabolic response to stress, including regulation of oxidative and metabolic stress and thermotolerance. The bovine chromosomal areas carrying QTLs for cattle trypanotolerance were compared with the regions on which the orthologous functional candidate cattle genes were located. The importance of cattle BTA4 for trypanotolerant response might have been conserved between species. The current research provides new insights on the genomic basis for adaptation and highlights the importance of obtaining information from non-cosmopolite livestock populations managed in harsh environments.


Assuntos
Genômica , Locos de Características Quantitativas/genética , Seleção Genética , Carneiro Doméstico/genética , Aclimatação/genética , Adaptação Fisiológica/genética , Animais , Evolução Biológica , Cruzamento , Domesticação , Humanos , Gado , Polimorfismo de Nucleotídeo Único/genética , Ovinos/genética , Carneiro Doméstico/fisiologia , Trypanosoma congolense/patogenicidade , Tripanossomíase Africana/genética , Tripanossomíase Africana/parasitologia
13.
Nat Commun ; 11(1): 844, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051413

RESUMO

African trypanosomes (Trypanosoma) are vector-borne haemoparasites that survive in the vertebrate bloodstream through antigenic variation of their Variant Surface Glycoprotein (VSG). Recombination, or rather segmented gene conversion, is fundamental in Trypanosoma brucei for both VSG gene switching and for generating antigenic diversity during infections. Trypanosoma vivax is a related, livestock pathogen whose VSG lack structures that facilitate gene conversion in T. brucei and mechanisms underlying its antigenic diversity are poorly understood. Here we show that species-wide VSG repertoire is broadly conserved across diverse T. vivax clinical strains and has limited antigenic repertoire. We use variant antigen profiling, coalescent approaches and experimental infections to show that recombination plays little role in diversifying T. vivax VSG sequences. These results have immediate consequences for both the current mechanistic model of antigenic variation in African trypanosomes and species differences in virulence and transmission, requiring reconsideration of the wider epidemiology of animal African trypanosomiasis.


Assuntos
Variação Antigênica/genética , Variação Antigênica/imunologia , Recombinação Genética/genética , Trypanosoma vivax/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/imunologia , DNA de Protozoário , Evolução Molecular , Genoma de Protozoário , Interações Hospedeiro-Parasita/imunologia , Evasão da Resposta Imune , Filogenia , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Homologia de Sequência , Especificidade da Espécie , Transcriptoma , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/parasitologia , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo
14.
Parasitol Res ; 119(3): 805-813, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006230

RESUMO

Addressing the problems linked to tsetse-transmitted trypanosomiases requires considerable data on tsetse distribution and trypanosome infections. Although efforts to map tsetse and trypanosome infections have been undertaken at continental level, published data are still rare in wildlife reserves of West and Central Africa. To fill this gap, data on tsetse distribution and trypanosome infections were generated in the wildlife reserve of Santchou. For this study, each tsetse caught was identified and its DNA extracted. Different trypanosome species were identified by PCR. Entomological and parasitological data were transported onto a satellite image in order to visualize their distributions. From 195 Glossina palpalis palpalis that were caught, 33.8% (66/195) carried trypanosome infections with 89.4% (59/66) of single infections and 10.6% (7/66) mixed infections. From the 66 flies with trypanosome infections, 54.5% (36/66), 27.3% (18/66) and 18.2% (12/66) were respectively due to Trypanosoma congolense, Trypanosoma brucei s.l. and Trypanosoma vivax. The global infection rates were 18.5% (36/195) for Trypanosoma congolense (forest and savannah), 9.2% (18/195) for Trypanosoma brucei s.l. and 6.1% (12/195) for Trypanosoma vivax. The maps generated show the distribution of tsetse and trypanosome infections. This study showed an active transmission of trypanosomes in the wildlife reserve of Santchou. The maps enabled to identify areas with high transmission risk and where control operations must be implemented in order to eliminate tsetse and the diseases that they transmit.


Assuntos
Animais Selvagens/parasitologia , Insetos Vetores/parasitologia , Trypanosoma/genética , Tripanossomíase Africana/veterinária , Moscas Tsé-Tsé/parasitologia , Animais , Camarões/epidemiologia , DNA de Protozoário/genética , Insetos Vetores/genética , Insetos Vetores/fisiologia , Reação em Cadeia da Polimerase , Trypanosoma/classificação , Trypanosoma/isolamento & purificação , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissão , Moscas Tsé-Tsé/genética , Moscas Tsé-Tsé/fisiologia
15.
Trends Parasitol ; 36(3): 266-278, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014419

RESUMO

African trypanosomes are mainly transmitted by tsetse flies. In recent years there has been good progress in understanding how the parasites prepare for transmission, detect their changed environment through the perception of different environmental cues, and respond by changing their developmental gene expression. In this review, we discuss the different signals and signaling mechanisms used by the parasites to carry out the early events necessary for their establishment in the fly. We also compare Trypanosoma brucei and Trypanosoma congolense, parasites that share a common pathway in the early stages of fly colonization but apparently use different mechanisms to achieve this.


Assuntos
Meio Ambiente , Trypanosoma/fisiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissão , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transdução de Sinais/fisiologia , Trypanosoma/crescimento & desenvolvimento
16.
Lancet infect. dis ; 20(2): [E38-E46], Feb. 01, 2020.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1117170

RESUMO

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox­eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox­eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.


Assuntos
Humanos , Pentamidina/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomíase Africana/parasitologia , Líquido Cefalorraquidiano/parasitologia , Quimioterapia Combinada
18.
Eur J Med Chem ; 189: 112043, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978782

RESUMO

Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC50 < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.


Assuntos
Ciclo Celular/efeitos dos fármacos , Distamicinas/química , Macrófagos/efeitos dos fármacos , Tiazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Tiazóis/química , Tripanossomicidas/química , Trypanosoma/parasitologia , Tripanossomíase Africana/parasitologia
19.
Proc Natl Acad Sci U S A ; 117(5): 2613-2621, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964820

RESUMO

Tsetse-transmitted African trypanosomes must develop into mammalian-infectious metacyclic cells in the fly's salivary glands (SGs) before transmission to a new host. The molecular mechanisms that underlie this developmental process, known as metacyclogenesis, are poorly understood. Blocking the few metacyclic parasites deposited in saliva from further development in the mammal could prevent disease. To obtain an in-depth perspective of metacyclogenesis, we performed single-cell RNA sequencing (scRNA-seq) from a pool of 2,045 parasites collected from infected tsetse SGs. Our data revealed three major cell clusters that represent the epimastigote, and pre- and mature metacyclic trypanosome developmental stages. Individual cell level data also confirm that the metacyclic pool is diverse, and that each parasite expresses only one of the unique metacyclic variant surface glycoprotein (mVSG) coat protein transcripts identified. Further clustering of cells revealed a dynamic transcriptomic and metabolic landscape reflective of a developmental program leading to infectious metacyclic forms preadapted to survive in the mammalian host environment. We describe the expression profile of proteins that regulate gene expression and that potentially play a role in metacyclogenesis. We also report on a family of nonvariant surface proteins (Fam10) and demonstrate surface localization of one member (named SGM1.7) on mature metacyclic parasites. Vaccination of mice with recombinant SGM1.7 reduced parasitemia early in the infection. Future studies are warranted to investigate Fam10 family proteins as potential trypanosome transmission blocking vaccine antigens. Our experimental approach is translationally relevant for developing strategies to prevent other insect saliva-transmitted parasites from infecting and causing disease in mammalian hosts.


Assuntos
Insetos Vetores/parasitologia , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/crescimento & desenvolvimento , Trypanosoma brucei brucei/genética , Moscas Tsé-Tsé/parasitologia , Animais , Feminino , Humanos , Estágios do Ciclo de Vida , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/imunologia , RNA de Protozoário/genética , Glândulas Salivares/parasitologia , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/parasitologia
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