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1.
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
4.
Parasit Vectors ; 12(1): 481, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31610794

RESUMO

BACKGROUND: Trypanosomes cause disease in humans and livestock in sub-Saharan Africa and rely on tsetse flies as their main insect vector. Nigeria is the most populous country in Africa; however, only limited information about the occurrence and diversity of trypanosomes circulating in the country is available. METHODS: Tsetse flies were collected from five different locations in or adjacent to protected areas, i.e. national parks and game reserves, in Nigeria. Proboscis and gut samples were analysed for trypanosome DNA by molecular amplification of the internal transcribed spacer 1 (ITS1) region and part of the trypanosome specific glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) gene. RESULTS: The most abundant Trypanosoma species found in the tsetse gut was T. grayi, a trypanosome infecting crocodiles. It was ubiquitously distributed throughout the country, accounting for over 90% of all cases involving trypanosomes. Trypanosoma congolense was detected in gut samples from all locations except Cross River National Park, but not in the proboscis, while T. brucei (sensu lato) was not detected at all. In proboscis samples, T. vivax was the most prominent. The sequence diversity of gGAPDH suggests that T. vivax and T. grayi represent genetically diverse species clusters. This implies that they are highly dynamic populations. CONCLUSIONS: The prevalence of animal pathogenic trypanosomes throughout Nigeria emphasises the role of protected areas as reservoirs for livestock trypanosomes. The genetic diversity observed within T. vivax and T. grayi populations might be an indication for changing pathogenicity or host range and the origin and consequences of this diversity has to be further investigated.


Assuntos
Variação Genética , Insetos Vetores/parasitologia , Trypanosoma/genética , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/parasitologia , Animais , DNA Intergênico/química , DNA Intergênico/isolamento & purificação , DNA de Protozoário/isolamento & purificação , Humanos , Insetos Vetores/classificação , Nigéria/epidemiologia , Filogenia , Reação em Cadeia da Polimerase , Prevalência , Especificidade da Espécie , Trypanosoma/classificação , Trypanosoma/isolamento & purificação , Trypanosoma congolense/classificação , Trypanosoma congolense/genética , Trypanosoma congolense/isolamento & purificação , Trypanosoma vivax/classificação , Trypanosoma vivax/genética , Trypanosoma vivax/isolamento & purificação , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/transmissão , Moscas Tsé-Tsé/classificação
5.
BMC Vet Res ; 15(1): 344, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619238

RESUMO

BACKGROUND: African animal trypanosomosis remains the major constraint of livestock production and livelihood of pastoral communities in Cameroon. Despite several decades of vector and parasite control efforts, it has not been eradicated. Alternative and sustainable control strategies require a sound knowledge of the local species, strains and vectors. In the Sudano-Sahelian and Guinea Savannah of Cameroon the prevalence and genetic diversity of trypanosomes infecting cattle was investigated by microscopy of cattle blood buffy coat and molecular methods using generic primers targeting parts of the internal transcribed spacer 1 (ITS-1) and encoded glycosomal glyceraldehyde 3-phosphate dehydrogenase-gene (gGAPDH). RESULTS: A total of 1176 randomly chosen cattle from five divisions in the Sudano-Sahelian and Guinea Savannah of Cameroon were examined. The overall prevalence of trypanosomes by microscopy was 5.9% (56/953) in contrast to 53.2% (626/1176) when molecular tools were used. This indicated a limited sensitivity of microscopy in subclinical infections with frequently low parasitemia. Three trypanosome species were identified by light microscopy: T. vivax (2.3%), T. brucei (3.7%) and T. congolense (3.0%), whereas five were identified by PCR, namely T. grayi/T. theileri (30.8%), T. vivax (17.7%), T. brucei (14.5%) and T. congolense (5.1%). Unexpected cases of T. grayi (n = 4) and T. theileri (n = 26) were confirmed by sequencing. Phylogenetic analysis of the gGAPDH revealed the presence of T. vivax, clade A and T. vivax clade C, which were co-endemic in the Faro et Deo division. T. grayi/T. theileri were the predominant species infecting cattle in tsetse free areas. In contrast, T. vivax, T. brucei and T. congolense were more abundant in areas where the Glossina-vectors were present. CONCLUSIONS: The abundance of pathogenic trypanosomes in tsetse infested areas is alarming and even more, the occurrence of T. vivax, T. brucei, T. congolense, T. theileri and T. grayi in tsetse-free areas implies that tsetse control alone is not sufficient to control trypanosomosis in livestock. To implement control measures that reduce the risk of spread in tsetse free areas, close monitoring using molecular tools and a thorough search for alternative vectors of trypanosomes is recommended.


Assuntos
Doenças dos Bovinos/epidemiologia , Trypanosoma/isolamento & purificação , Tripanossomíase Africana/epidemiologia , Animais , Buffy Coat/parasitologia , Camarões/epidemiologia , Bovinos , Doenças dos Bovinos/parasitologia , Feminino , Genes de Protozoários , Insetos Vetores , Masculino , Prevalência , Trypanosoma/classificação , Trypanosoma/genética , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/prevenção & controle , Moscas Tsé-Tsé
6.
Biochimie ; 167: 207-216, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31628976

RESUMO

Oligopeptidases B (OPB) belong to the S9 prolyl oligopeptidase family and are expressed in prokaryotes, some eukaryotes and in some higher plants. OPB is not found in any of the mammalian genomes available to date. Evidences indicate that OPB participates in the infections caused by trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp and therefore it is considered an important virulence factor. Trypanosomatids from the genera Leishmania and Trypanosoma also present other OPB, named OPB2. A more accurate investigation of trypanosomatid OPB sequences brought attention to what could be a third OPB sequence (OPB3). This review aims to discuss biochemical, structural, phylogenetic and functional properties of OPB and its potential as target for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.


Assuntos
Leishmania/enzimologia , Serina Endopeptidases , Trypanosoma brucei brucei/enzimologia , Trypanosoma cruzi/enzimologia , Fatores de Virulência , Animais , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Mamíferos , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Serina Endopeptidases/química , Serina Endopeptidases/classificação , Serina Endopeptidases/imunologia , Tripanossomíase Africana/parasitologia , Fatores de Virulência/química , Fatores de Virulência/classificação , Fatores de Virulência/imunologia
7.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374887

RESUMO

Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.


Assuntos
Antiparasitários/uso terapêutico , Leishmaniose/tratamento farmacológico , Tiocarbamatos/uso terapêutico , Trypanosoma/efeitos dos fármacos , Animais , Antiparasitários/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Tiocarbamatos/química , Trypanosoma/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
8.
Exp Parasitol ; 205: 107753, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31469986

RESUMO

Trypanosoma brucei causes human African trypanosomiasis and Nagana disease in cattle, imposing substantial medical and economic burden in sub-Saharan Africa. The current treatments have limitations, including the requirement for elaborated protocols, development of drug resistance, and they are prone to adverse side effects. In vitro screening of a library of 14 dinuclear-thiolato bridged arene ruthenium complexes, originally developed for treatment of cancer cells, resulted in the identification of 7 compounds with IC50 values ranging from 3 to 26 nM. Complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-o-Pri)3]Cl (2) (IC50 = 4 nM) and complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SCH2C6H4-p-But)2(µ2-SC6H4-p-OH)]BF4(9) (IC50 = 26 nM) were chosen for further assessments. Application of complex 2 and 9 at 20 nM and 200 nM, respectively, for 4.5 h induced alterations in the trypanosome mitochondrion as evidenced by immunofluorescence employing an antibody against mitochondrial Hsp70 and Mitotracker labeling. Transmission electron microscopy of parasites taken at 2 and 4h of treatment demonstrated massive alterations in the mitochondrial ultrastructure, while other organelles and structural elements of the parasites remained unaffected. Complex 2 treated trypanosomes exhibited a distorted mitochondrial membrane, and the mitochondrial matrix was transformed into an amorphous mass with different degrees of electron densities. Complex 9 did not notably impair the integrity of the membrane, but the interior of the mitochondrion appeared either completely translucent, or was filled with filamentous structures of unknown nature. Dose- and time-dependent effects of these two compounds on the mitochondrial membrane potential were detected by tetramethylrhodamine ethyl ester assay. Thus, the mitochondrion and associated metabolic processes are an important target of dinuclear thiolato-bridged arene ruthenium complexes in T. brucei.


Assuntos
Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia , Animais , Relação Dose-Resposta a Droga , Imunofluorescência , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Compostos de Rutênio/química , Fatores de Tempo , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei brucei/ultraestrutura , Tripanossomíase Africana/sangue
9.
Nat Commun ; 10(1): 3023, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289266

RESUMO

The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.


Assuntos
Variação Antigênica/genética , Epigênese Genética/imunologia , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/genética , Alelos , Animais , Variação Antigênica/imunologia , Linhagem Celular , Fator 1 de Modelagem da Cromatina/imunologia , Fator 1 de Modelagem da Cromatina/metabolismo , Replicação do DNA/imunologia , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Evasão da Resposta Imune , Proteínas de Protozoários/imunologia , Transcrição Genética/imunologia , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/parasitologia , Glicoproteínas Variantes de Superfície de Trypanosoma/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo
10.
PLoS Negl Trop Dis ; 13(7): e0007568, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31344039

RESUMO

The tsetse fly, Glossina morsitans morsitans, is a significant problem in Zambia and Malawi. It is the vector for the human infective parasite Trypanosoma brucei rhodesiense, which causes human African trypanosomiasis, and various Trypanosoma species, which cause African animal trypanosomiasis. Understanding the genetic diversity and population structure of G. m. morsitans is the basis of elucidating the connectivity of the tsetse fly populations, information that is essential in implementing successful tsetse fly control activities. This study conducted a population genetic study using partial mitochondrial cytochrome oxidase gene 1 (CO1) and 10 microsatellite loci to investigate the genetic diversity and population structure of G. m. morsitans captured in the major HAT foci in Zambia and Malawi. We have included 108 and 99 G. m. morsitans samples for CO1 and microsatellite analyses respectively. Our results suggest the presence of two different genetic clusters of G. m. morsitans, existing East and West of the escarpment of the Great Rift Valley. We have also revealed genetic similarity between the G. m. morsitans in Kasungu National Park and those in the Luangwa river basin in Zambia, indicating that this population should also be included in this historical tsetse belt. Although further investigation is necessary to illustrate the whole picture in East and Southern Africa, this study has extended our knowledge of the population structure of G. m. morsitans in Southern Africa.


Assuntos
Variação Genética , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/genética , Animais , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Genética Populacional , Haplótipos , Humanos , Insetos Vetores/genética , Malaui , Masculino , Repetições de Microssatélites , Filogeografia , Moscas Tsé-Tsé/enzimologia , Zâmbia
11.
PLoS One ; 14(5): e0217828, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150492

RESUMO

The discovery of 20 unconventional kinetochore proteins in Trypanosoma brucei has opened a new and interesting area of evolutionary research to study a biological process previously thought to be highly conserved in all eukaryotes. In addition, the discovery of novel proteins involved in a critical cellular process provides an opportunity to exploit differences between kinetoplastid and human kinetochore proteins to develop therapeutics for diseases caused by kinetoplastid parasites. Consequently, we identified two of the unconventional kinetochore proteins as key targets (the highly related kinases KKT10 and KKT19). Recombinant T. brucei KKT19 (TbKKT19) protein was produced, a peptide substrate phosphorylated by TbKKT19 identified (KKLRRTLSVA), Michaelis constants for KKLRRTLSVA and ATP were determined (179 µM and 102 µM respectively) and a robust high-throughput compatible biochemical assay developed. This biochemical assay was validated pharmacologically with inhibition by staurosporine and hypothemycin (IC50 values of 288 nM and 65 nM respectively). Surprisingly, a subsequent high-throughput screen of a kinase-relevant compound library (6,624 compounds) yielded few hits (8 hits; final hit rate 0.12%). The low hit rate observed was unusual for a kinase target, particularly when screened against a compound library enriched with kinase hinge binding scaffolds. In an attempt to understand the low hit rate a TbKKT19 homology model, based on human cdc2-like kinase 1 (CLK1), was generated. Analysis of the TbKKT19 sequence and structure revealed no obvious features that could explain the low hit rates. Further work will therefore be necessary to explore this unique kinetochore kinase as well as to assess whether the few hits identified can be developed into tool molecules or new drugs.


Assuntos
Peptídeos/antagonistas & inibidores , Fosfotransferases/antagonistas & inibidores , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/dietoterapia , Animais , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Cinetocoros/efeitos dos fármacos , Cinetocoros/enzimologia , Peptídeos/química , Fosfotransferases/química , Fosfotransferases/genética , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Estaurosporina/farmacologia , Trypanosoma brucei brucei/enzimologia , Tripanossomíase Africana/parasitologia , Zearalenona/análogos & derivados , Zearalenona/farmacologia
12.
PLoS One ; 14(6): e0218441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220132

RESUMO

Experiments on infections caused by trypanosomes are widely performed in Swiss white mice through various inoculation routes. To better understand the effect of route of trypanosome inoculation on disease outcomes in this model, we characterised the virulence of two isolates, Trypanosoma brucei KETRI 2710 and T. congolense KETRI 2765 in Swiss white mice. For each of the isolates, five routes of parasite inoculation, namely intraperitoneal (IP), subcutaneous (SC), intramuscular (IM) intradermal (ID) and intravenous (IV) were compared using groups (n = 6) of mice, with each mouse receiving 1x104 trypanosomes. We subsequently assessed impact of the routes on disease indices that included pre-patent period (PP), parasitaemia levels, Packed Cell Volume (PCV), bodyweight changes and survival time. Pre-patent period for IP inoculated mice was a mean ± SE of 3.8 ± 0.2 and 6.5 ± 0.0 for the T brucei and T. congolense isolates respectively; the PP for mice groups inoculated using other routes were not significantly different(p> 0.05) irrespective of route of inoculation and species of trypanosomes. With ID and IP routes, parasitaemia was significantly higher in T. brucei and significantly lower in T. congolense infected mice and the progression to peak parasitaemia routes showed no significant different between the routes of either species of trypanosome. The IM and ID routes in T. congolense inoculations, and IP and IV in T. b. brucei induced the fastest and slowest parasitaemia progressions respectively. There were significant differences in rates of reduction of PCV with time post infection in mice infected by the two species and which was more pronounced in sc and ip injected mice. No significant differences in mice body weight changes and survivorship was observed between the routes of inoculation. Inoculation route therefore appears to be a critical determinant of pathogenicity of Trypanosoma congolense and Trypanosoma brucei brucei in murine mouse model of African trypanosomiasis.


Assuntos
Parasitemia/parasitologia , Trypanosoma brucei brucei/patogenicidade , Trypanosoma congolense/patogenicidade , Tripanossomíase Africana/parasitologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Parasitemia/transmissão , Tripanossomíase Africana/transmissão , Vacinação , Virulência
13.
Nucleic Acids Res ; 47(13): 7063-7077, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31127277

RESUMO

Post-transcriptional regulons coordinate the expression of groups of genes in eukaryotic cells, yet relatively few have been characterized. Parasitic trypanosomatids are particularly good models for studies on such mechanisms because they exhibit almost exclusive polycistronic, and unregulated, transcription. Here, we identify the Trypanosoma brucei ZC3H39/40 RNA-binding proteins as regulators of the respiratome; the mitochondrial electron transport chain (complexes I-IV) and the FoF1-ATP synthase (complex V). A high-throughput RNAi screen initially implicated both ZC3H proteins in variant surface glycoprotein (VSG) gene silencing. This link was confirmed and both proteins were shown to form a cytoplasmic ZC3H39/40 complex. Transcriptome and mRNA-interactome analyses indicated that the impact on VSG silencing was indirect, while the ZC3H39/40 complex specifically bound and stabilized transcripts encoding respiratome-complexes. Quantitative proteomic analyses revealed specific positive control of >20 components from complexes I, II and V. Our findings establish a link between the mitochondrial respiratome and VSG gene silencing in bloodstream form T. brucei. They also reveal a major respiratome regulon controlled by the conserved trypanosomatid ZC3H39/40 RNA-binding proteins.


Assuntos
Respiração Celular/fisiologia , Regulação da Expressão Gênica/genética , Proteínas de Protozoários/fisiologia , Proteínas de Ligação a RNA/fisiologia , Regulon/fisiologia , Trypanosoma brucei brucei/fisiologia , Adaptação Fisiológica , Sequência de Aminoácidos , Transporte de Elétrons/fisiologia , Inativação Gênica , Humanos , Mitocôndrias/metabolismo , Parasitemia/parasitologia , Mapeamento de Interação de Proteínas , Proteômica/métodos , ATPases Translocadoras de Prótons/fisiologia , Interferência de RNA , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transcriptoma , Trypanosoma brucei brucei/isolamento & purificação , Tripanossomíase Africana/parasitologia , Glicoproteínas Variantes de Superfície de Trypanosoma/biossíntese , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
14.
Korean J Parasitol ; 57(2): 191-195, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31104413

RESUMO

Trypanosomiasis is caused by a pathogenic protozoan of the genus Trypanosoma, being Trypanosoma vivax the most important agent for cattle. The aim of the present study was to demonstrate the expansion of T. vivax infection in different mesoregions of Minas Gerais, Brazil, and describe the clinicopathological findings of trypanosomiasis in cattle. The diagnosis was based on visualization of the parasite in blood smears and DNA detection of T. vivax in the blood of live cows and tissues of necropsied animals by the polymerase chain reaction (PCR). Thirty suspected herds were tested, of which 11 were positive for T. vivax. The most frequent clinical signs were anemia, apathy, drop in milk production, weight loss, reproductive disorders, and nervous signs. Concomitant diseases, such as malignant edema, pneumonia and increased cases of mastitis were associated with T. vivax infection. Three cows were necropsied and the most significant findings were low body condition score, pale mucous and spleen with white pulp hyperplasia. The results demonstrated the expansion of T. vivax infection in Minas Gerais, that PCR-associated blood smears are promising for diagnosis, and that other diseases often occur concomitantly to T. vivax infection in regions with trypanosomiasis in cattle.


Assuntos
Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/patologia , Trypanosoma vivax/isolamento & purificação , Tripanossomíase Africana/veterinária , Estruturas Animais/parasitologia , Estruturas Animais/patologia , Animais , Sangue/parasitologia , Brasil/epidemiologia , Bovinos , Doenças dos Bovinos/parasitologia , Microscopia , Reação em Cadeia da Polimerase , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/patologia
15.
Dev Comp Immunol ; 98: 181-188, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075296

RESUMO

Tsetse flies (Glossina sp.) are medically and veterinary important vectors of African trypanosomes, protozoan parasites that cause devastating diseases in humans and livestock in sub-Saharan Africa. These flies feed exclusively on vertebrate blood and harbor a limited diversity of obligate and facultative bacterial commensals. They have a well-developed innate immune system that plays a key role in protecting the fly against invading pathogens and in modulating the fly's ability to transmit African trypanosomes. In this review, we briefly summarize our current knowledge on the tsetse fly innate immune system and its interaction with the bacterial commensals and the trypanosome parasite.


Assuntos
Imunidade Inata , Insetos Vetores/imunologia , Trypanosoma/imunologia , Tripanossomíase Africana/imunologia , Moscas Tsé-Tsé/imunologia , Animais , Bactérias/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Insetos Vetores/microbiologia , Insetos Vetores/parasitologia , Simbiose/imunologia , Trypanosoma/microbiologia , Trypanosoma/fisiologia , Tripanossomíase Africana/microbiologia , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/microbiologia , Moscas Tsé-Tsé/parasitologia
16.
PLoS Negl Trop Dis ; 13(5): e0007373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120889

RESUMO

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antiprotozoários/administração & dosagem , Benzodiazepinas/administração & dosagem , Pirróis/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antiprotozoários/química , Benzodiazepinas/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/química , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
17.
PLoS One ; 14(5): e0216078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048849

RESUMO

African trypanosomiasis remains a lethal disease to both humans and livestock. The disease persists due to limited drug availability, toxicity and drug resistance, hence the need for a better understanding of the parasite's biology and provision of alternative forms of therapy. In this study, the in vitro effects of phenolic acids were assessed for their trypanocidal activities against Trypanosoma brucei brucei. The effect of the phenolic acids on Trypanosoma brucei brucei was determined by the alamarBlue assay. The cell cycle effects were determined by flow cytometry and parasite morphological analysis was done by microscopy. Effect on cell proliferation was determined by growth kinetic analysis. Reverse Transcriptase quantitative Polymerase Chain Reaction was used to determine expression of iron dependent enzymes and iron distribution determined by atomic absorption spectroscopy. Gallic acid gave an IC50 of 14.2±1.5 µM. Deferoxamine, gallic acid and diminazene aceturate showed a dose dependent effect on the cell viability and the mitochondrion membrane integrity. Gallic acid, deferoxamine and diminazene aceturate caused loss of kinetoplast in 22%, 26% and 82% of trypanosomes respectively and less than 10% increase in the number of trypanosomes in S phase was observed. Gallic acid caused a 0.6 fold decrease, 50 fold increase and 7 fold increase in the expression levels of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes respectively while treatment with deferoxamine and diminazene aceturate also showed differential expressions of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes. The data suggests that gallic acid possibly exerts its effect on T. brucei via iron chelation leading to structural and morphological changes and arrest of the cell cycle. These together provide information on the cell biology of the parasite under iron starved conditions and provide leads into alternative therapeutic approaches in the treatment of African trypanosomiasis.


Assuntos
Hidroxibenzoatos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Diminazena/análogos & derivados , Diminazena/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Ácido Gálico/farmacologia , Humanos , Ferro/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma/efeitos dos fármacos , Trypanosoma brucei brucei/patogenicidade , Tripanossomíase Africana/parasitologia
18.
Parasite Immunol ; 41(8): e12632, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31099071

RESUMO

Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main etiological agent of human African trypanosomiasis (HAT) or sleeping sickness. Dendritic cells (DCs) play a pivotal role at the interface between innate and adaptive immune response and are implicated during HAT. In this study, we investigated the effects of T gambiense and its excreted/secreted factors (ESF) on the phenotype of human monocyte-derived DCs (Mo-DCs). Mo-DCs were cultured with trypanosomes, lipopolysaccharide (LPS), ESF derived from T gambiense bloodstream strain Biyamina (MHOM/SD/82), or both ESF and LPS. Importantly, ESF reduced the expression of the maturation markers HLA-DR and CD83, as well as the secretion of IL-12, TNF-alpha and IL-10, in LPS-stimulated Mo-DCs. During mixed-leucocyte reactions, LPS- plus ESF-exposed DCs induced a non-significant decrease in the IFN-gamma/IL-10 ratio of CD4 + T-cell cytokines. Based on the results presented here, we raise the hypothesis that T gambiense has developed an immune escape strategy through the secretion of paracrine mediators in order to limit maturation and activation of human DCs. The identification of the factor(s) in the T gambiense ESF and of the DCs signalling pathway(s) involved may be important in the development of new therapeutic targets.


Assuntos
Células Dendríticas/imunologia , Monócitos/imunologia , Proteínas de Protozoários/imunologia , Trypanosoma brucei gambiense/imunologia , Tripanossomíase Africana/imunologia , Animais , Células Dendríticas/parasitologia , Feminino , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Interações Hospedeiro-Parasita , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Monócitos/parasitologia , Proteínas de Protozoários/genética , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/parasitologia , Trypanosoma brucei gambiense/genética , Tripanossomíase Africana/genética , Tripanossomíase Africana/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
Exp Parasitol ; 201: 49-56, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31029700

RESUMO

Trypanosoma congolense is an important pathogen that wreaks havoc in the livestock industry of the African continent. This study evaluated the in vivo antitrypanosomal activity of geranylacetone and its ameliorative effect on the disease-induced anaemia and organ damages as well as its inhibitory effects against trypanosomal sialidase using in vitro and in silico techniques. Geranylacetone was used to treat T. congolense infected rats, at a dose of 50 and 100 mg/kg BW, for 14 days where it was found to reduce the parasite burden in the infected animals. Moreover, 100 mg/kg BW of geranylacetone significantly (p < 0.05) ameliorated the anaemia, hepatic and renal damages caused by the parasite. This is in addition to the alleviation of the parasite-induced hepatosplenomegaly and upsurge in free serum sialic acid levels in the infected animals which were associated with the observed anaemia amelioration by the compound. Consequently, bloodstream T. congolense sialidase was partially purified on DEAE cellulose column and inhibition kinetic studies revealed that the enzyme was inhibited by geranylacetone via an uncompetitive inhibition pattern. In silico analysis using molecular docking with Autodock Vina indicated that geranylacetone binds to trypanosomal sialidase with a minimum free binding energy of -5.8 kcal/mol which was mediated by 26 different kinds of non-covalent interactions excluding hydrogen bond whilst Asp163 and Phe421 had the highest number of the interactions. The data suggests that geranylacetone has trypanostatic activity and could protect animals against the T. congolense-induced anaemia through the inhibition of sialidase and/or the protection of the parasite-induced hepatosplenomegaly.


Assuntos
Anemia/prevenção & controle , Terpenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/parasitologia , Animais , Feminino , Coração/efeitos dos fármacos , Coração/parasitologia , Concentração Inibidora 50 , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Masculino , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Rubiaceae/química , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Terpenos/química , Terpenos/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia
20.
Int J Mol Sci ; 20(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934540

RESUMO

The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.


Assuntos
Descoberta de Drogas , Interações Hospedeiro-Parasita , Glicoproteínas de Membrana/metabolismo , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Animais , Humanos , Proteólise
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