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1.
Trop Anim Health Prod ; 54(6): 370, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36323989

RESUMO

Control programmes for African animal trypanosomiasis (AAT) in livestock have been mainly focused on cattle with very little focus on goats, an important reservoir for the disease. Using the polymerase chain reaction (PCR), this study investigated trypanosome infection in village goats in Mambwe, a rural District in Eastern Zambia. Filter paper blood spots were collected from 326 goats and tested for infection with Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei s.l. using ribosomal RNA internal transcribed spacers (ITS)-PCR. The frequency of trypanosomes from the sampled goats was 4.6% (95% CI = 2.3-6.8). Results indicated significantly high infections with Trypanosoma vivax (4.0%; 95% CI = 1.9-6.1) than T. congolense (0.6%; 95% CI = - 0.2 to 1.5), and T. brucei (0.0%), P = 0.04. Findings show the circulation of trypanosomes that causes AAT in goats and that they may pose serious threats to not only goats but also to other livestock reared alongside goats.


Assuntos
Doenças das Cabras , Trypanosoma congolense , Trypanosoma , Tripanossomíase Africana , Moscas Tsé-Tsé , Bovinos , Animais , Cabras , Zâmbia/epidemiologia , Trypanosoma/genética , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária , Trypanosoma vivax , Gado , Doenças das Cabras/epidemiologia
2.
Vet Parasitol Reg Stud Reports ; 35: 100783, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184110

RESUMO

Animal African Trypanosomiasis (AAT) remains an animal health problem in sub-Saharan Africa and in Cameroon in particular. Despite more than 40 years of fighting against AAT in some tsetse infested areas, the disease prevalence is still a concern. Improving the control strategies in different settings requires to understand the current epidemiological situation of AAT. The aim of the present study was to update our knowledge on the diversity of tsetse fauna and trypanosome species in the tsetse infested area of Faro and Deo division, Adamawa region, Cameroon. Tsetse flies were caught using Vavoua trap in two villages and the apparent density per trap (ADP) were estimated. After morphological identification of tsetse fly species, flies were dissected and their midguts recovered. The presence of blood meal residues was recorded. Trypanosomes species were checked in the flies' midguts by microscopy followed by PCR method. The vertebrate taxa on which tsetse flies have taken blood meal were determined using the heteroduplex-PCR method. A total of 338 tsetse flies including 11 teneral flies (10 Glossina palpalis palpalis and 01 G. morsitans submorsitans) and 327 non-teneral were trapped in Mayo Lainde and Tchabal Mbabo. Amongst the caught tsetse flies, of the 327 non-teneral flies, 315 (96.3%) were G. p. palpalis, 8 (2.4%) were G. morsitans submorsitans and 4 (1.2%) G. fuscipes fuscipes. Trypanosome infections including Trypanosoma congolense forest (19.88%) and savanah (2.53%) "types", T. brucei s.l. (7.30%) and T. vivax (2.85%) were identified in 45.08% of non-teneral flies (32.38% for single infection and 12.70% for mixed infection). Amongst the 54 blood meals identified in tsetse midguts, 41% were from humans, 33% from cattle and 26% from other vertebrate hosts. About 51.9% of blood meals were found with various trypanosome species including 42.6% with T. congolense and 24% with T. brucei s.l. This study revealed the presence of three tsetse taxa and the circulation of four trypanosome taxa in villages of the Faro and Deo division. About 45% of captured tsetse fly are infected with trypanosome species causing AAT. Tsetse flies feed on humans, cattle and many other vertebrates. Strategies to eliminate the vectors must be improved to reduce the pathological impacts of trypanosome infections in this area.


Assuntos
Doenças dos Bovinos , Trypanosoma congolense , Tripanossomíase Africana , Moscas Tsé-Tsé , Difosfato de Adenosina , Animais , Camarões/epidemiologia , Bovinos , Doenças dos Bovinos/epidemiologia , Humanos , Insetos Vetores , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária
3.
PLoS Negl Trop Dis ; 16(8): e0010106, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35994491

RESUMO

BACKGROUND: Animal African Trypanosomosis (AAT) is a parasitic disease of livestock that has a major socio-economic impact in the affected areas. It is caused by several species of uniflagellate extracellular protists of the genus Trypanosoma mainly transmitted by tsetse flies: T. congolense, T. vivax and T. brucei brucei. In Burkina Faso, AAT hampers the proper economic development of the southwestern part of the country, which is yet the best watered area particularly conducive to agriculture and animal production. It was therefore important to investigate the extent of the infection in order to better control the disease. The objective of the present study was to assess the prevalence of trypanosome infections and collect data on the presence of tsetse flies. METHODS: Buffy coat, Trypanosoma species-specific PCR, Indirect ELISA Trypanosoma sp and trypanolysis techniques were used on 1898 samples collected. An entomological survey was also carried out. RESULTS: The parasitological prevalence of AAT was 1.1%, and all observed parasites were T. vivax. In contrast, the molecular prevalence was 23%, of which T. vivax was predominant (89%) followed by T. congolense (12.3%) and T. brucei s.l. (7.3%) with a sizable proportion as mixed infections (9.1%). T. brucei gambiense, responsible of sleeping sickness in humans, was not detected. The serological prevalence reached 49.7%. Once again T. vivax predominated (77.2%), but followed by T. brucei (14.7%) and T. congolense (8.1%). Seven samples, from six cattle and one pig, were found positive by trypanolysis. The density per trap of Glossina tachinoides and G. palpalis gambiensis was 1.2 flies. CONCLUSIONS/SIGNIFICANCE: Overall, our study showed a high prevalence of trypanosome infection in the area, pointing out an ongoing inadequacy of control measures.


Assuntos
Trypanosoma congolense , Trypanosoma , Tripanossomíase Africana , Moscas Tsé-Tsé , Animais , Burkina Faso/epidemiologia , Bovinos , Humanos , Insetos Vetores/parasitologia , Epidemiologia Molecular , Suínos , Trypanosoma/genética , Trypanosoma congolense/genética , Trypanosoma vivax/genética , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária , Moscas Tsé-Tsé/parasitologia
4.
J Biol Chem ; 298(10): 102403, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35995210

RESUMO

Trypanosomes cause the devastating disease trypanosomiasis, in which the action of trans-sialidase (TS) enzymes harbored on their surface is a key virulence factor. TS enzymes are N-glycosylated, but the biological functions of their glycans have remained elusive. In this study, we investigated the influence of N-glycans on the enzymatic activity and structural stability of TconTS1, a recombinant TS from the African parasite Trypanosoma congolense. We expressed the enzyme in Chinese hamster ovary Lec1 cells, which produce high-mannose type N-glycans similar to the TS N-glycosylation pattern in vivo. Our MALDI-TOF mass spectrometry data revealed that up to eight putative N-glycosylation sites were glycosylated. In addition, we determined that N-glycan removal via endoglycosidase Hf treatment of TconTS1 led to a decrease in substrate affinity relative to the untreated enzyme but had no impact on the conversion rate. Furthermore, we observed no changes in secondary structure elements of hypoglycosylated TconTS1 in CD experiments. Finally, our molecular dynamics simulations provided evidence for interactions between monosaccharide units of the highly flexible N-glycans and some conserved amino acids located at the catalytic site. These interactions led to conformational changes, possibly enhancing substrate accessibility and enzyme-substrate complex stability. The here-observed modulation of catalytic activity via N-glycans represents a so-far-unknown structure-function relationship potentially inherent in several members of the TS enzyme family.


Assuntos
Glicoproteínas , Neuraminidase , Trypanosoma congolense , Animais , Cricetinae , Células CHO , Cricetulus , Glicosilação , Neuraminidase/metabolismo , Polissacarídeos/metabolismo , Trypanosoma congolense/enzimologia , Glicoproteínas/metabolismo
5.
Elife ; 112022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35787830

RESUMO

Trypanosoma congolense causes a syndrome of variable severity in animals in Africa. Cerebral trypanosomiasis is a severe form, but the mechanism underlying this severity remains unknown. We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral, and physiological consequences of this infection. We show large parasite sequestration in the brain vasculature for long periods of time (up to 8 hr) and extensive neuropathology that associate with ICAM1-mediated recruitment and accumulation of T cells in the brain parenchyma. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.


Assuntos
Parasitos , Trypanosoma congolense , Tripanossomíase Africana , Tripanossomíase , Animais , Modelos Animais de Doenças , Camundongos , Tripanossomíase Africana/parasitologia
6.
Vet Pathol ; 59(5): 773-781, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35656928

RESUMO

Trypanosomosis of the West African Dwarf (WAD) sheep is often neglected due to emphasis on trypanotolerance. Nevertheless, significant pathological changes may occur in tissues of infected WAD sheep. The purpose of this study was to evaluate the brain, pituitary, and adrenal lesions of Trypanosoma brucei brucei (Tbb) and Trypanosoma congolense (Tc) infections in WAD rams. Fifteen WAD rams were infected intraperitoneally with Tbb or Tc (106 trypanosomes/animal) or were uninfected controls (5 rams per group). Adrenocorticotrophic hormone (ACTH) and cortisol were assayed in serum by enzyme immunoassay technique. The brain, pituitary, and adrenal glands were processed for histopathology. Serum ACTH levels of infected rams were significantly (P < .05) higher than that of controls on days 14 and 70 post infection (PI). Serum cortisol levels of infected rams were significantly (P < .05) higher than that of controls only on day 14 PI. Mortality was 60% in Tbb- and 40% in Tc-infected rams. The brain of the infected groups showed chromatolysis of cortical neurons and Purkinje cells with severe encephalitis. Degenerative, necrotic, and inflammatory changes were seen in the pituitary and adrenal glands of the infected rams. Adrenal corticomedullary ratio was significantly (P < .05) higher in Tc-infected rams than controls. Based on the high mortality levels, likely due to severe encephalitis, the WAD sheep may not be regarded as trypanotolerant.


Assuntos
Encefalite , Doenças da Hipófise , Trypanosoma brucei brucei , Trypanosoma congolense , Tripanossomíase Africana , Hormônio Adrenocorticotrópico , Animais , Encefalite/veterinária , Hidrocortisona , Masculino , Doenças da Hipófise/veterinária , Hipófise , Ovinos , Carneiro Doméstico , Trypanosoma congolense/fisiologia , Tripanossomíase Africana/veterinária
7.
Parasit Vectors ; 15(1): 152, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501882

RESUMO

BACKGROUND: Animal African trypanosomiasis, or nagana, is a veterinary disease caused by African trypanosomes transmitted by tsetse flies. In Africa, Trypanosoma congolense is one of the most pathogenic and prevalent causes of nagana in livestock, resulting in high animal morbidity and mortality and extensive production losses. In the tsetse fly, parasites colonise the midgut and eventually reach the mouthparts, from where they can be transmitted as the fly feeds on vertebrate hosts such as cattle. Despite the extreme importance of mouthpart-form parasites for disease transmission, very few global expression profile studies have been conducted in these parasite forms. METHODS: Here, we collected tsetse flies from the Shimba Hills National Reserve, a wildlife area in southeast Kenya, diagnosed T. congolense infections, and sequenced the transcriptomes of the T. congolense parasites colonising the mouthparts of the flies. RESULTS: We found little correlation between mouthpart parasites from natural and experimental fly infections. Furthermore, we performed differential gene expression analysis between mouthpart and bloodstream parasite forms and identified several surface-expressed genes and 152 novel hypothetical proteins differentially expressed in mouthpart parasites. Finally, we profiled variant antigen expression and observed that a variant surface glycoprotein (VSG) transcript belonging to T. congolense phylotype 8 (i.e. TcIL3000.A.H_000381200), previously observed to be enriched in metacyclic transcriptomes, was present in all wild-caught mouthpart samples as well as bloodstream-form parasites, suggestive of constitutive expression. CONCLUSION: Our study provides transcriptomes of trypanosome parasites from naturally infected tsetse flies and suggests that a phylotype 8 VSG gene is constitutively expressed in metacyclic- and bloodstream-form parasites at the population level.


Assuntos
Dípteros , Parasitos , Trypanosoma congolense , Tripanossomíase Africana , Moscas Tsé-Tsé , Animais , Bovinos , Dípteros/genética , Humanos , Quênia , Glicoproteínas de Membrana/genética , Parasitos/genética , Transcriptoma , Trypanosoma congolense/genética , Moscas Tsé-Tsé/parasitologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-35567803

RESUMO

Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species. Compound 7, an inosine analogue, and our previously described lead compound, 3'-deoxytubercidin (8), showed broad spectrum anti-AT activity, metabolic stability in the target host species and absence of toxicity, but with variable efficacy ranging from limited activity to full cure in mouse models of Trypanosoma congolense and T. vivax infection. Several compounds show promise against T. evansi (surra) and T. equiperdum (dourine). Given the preferred target product profile for a broad-spectrum compound against AT, this study emphasizes the need to include T. vivax in the screening cascade given its divergent susceptibility profile and provides a basis for lead optimization towards such broad spectrum anti-AT compound.


Assuntos
Trypanosoma congolense , Trypanosoma , Tripanossomíase , Animais , Modelos Animais de Doenças , Resistência a Medicamentos , Camundongos , Nucleosídeos/uso terapêutico , Tripanossomíase/tratamento farmacológico , Tripanossomíase/parasitologia
9.
J Med Chem ; 65(7): 5606-5624, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35303411

RESUMO

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.


Assuntos
Trypanosoma congolense , Tripanossomíase Africana , Animais , Bovinos , Quinases Ciclina-Dependentes , Reposicionamento de Medicamentos , Trypanosoma vivax , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária
10.
Parasitology ; 149(3): 285-297, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35264263

RESUMO

The prevalence rates of trypanosomes, including those that require cyclical transmission by tsetse flies, are widely distributed in Africa. Trypanosoma brucei and Trypanosoma congolense are actively maintained in regions where there are no tsetse flies although at low frequencies. Whether this could be due to an independent evolutionary origin or multiple introduction of trypanosomes due to continuous movement of livestock between tsetse-free and -infested areas is not known. Thus, the aim of the study was to carry out microsatellite genotyping to explore intra-specific genetic diversity between T. (Trypanozoon), T. congolense and Trypanosoma vivax from the two regions: tsetse infested and tsetse free. Microsatellite genotyping showed geographical origin-based structuring among T. (Trypanozoon) isolates. There was a clear separation between isolates from the two regions signalling the potential of microsatellite markers as diagnostic markers for T. brucei and Trypanosoma evansi isolates. Trypanosoma vivax isolates also clustered largely based on the sampling location with a significant differentiation between the two locations. However, our results revealed that T. congolense isolates from Northern Kenya are not genetically separated from those from Coastal Kenya. Therefore, these isolates are likely introduced in the region through animal movement. Our results demonstrate the occurrence of both genetic connectivity as well as independent evolutionary origin, depending on the trypanosome species between the two ecologies.


Assuntos
Trypanosoma brucei brucei , Trypanosoma congolense , Trypanosoma , Tripanossomíase Africana , Moscas Tsé-Tsé , Animais , Quênia/epidemiologia , Trypanosoma/genética , Trypanosoma brucei brucei/genética , Trypanosoma congolense/genética , Trypanosoma vivax/genética , Tripanossomíase Africana/epidemiologia
11.
Int J Mol Sci ; 23(5)2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35269985

RESUMO

The animal trypanosomiases are infections in a wide range of (domesticated) animals with any species of African trypanosome, such as Trypanosoma brucei, T. evansi, T. congolense, T. equiperdum and T. vivax. Symptoms differ between host and infective species and stage of infection and are treated with a small set of decades-old trypanocides. A complication is that not all trypanosome species are equally sensitive to all drugs and the reasons are at best partially understood. Here, we investigate whether drug transporters, mostly identified in T. b. brucei, determine the different drug sensitivities. We report that homologues of the aminopurine transporter TbAT1 and the aquaporin TbAQP2 are absent in T. congolense, while their introduction greatly sensitises this species to diamidine (pentamidine, diminazene) and melaminophenyl (melarsomine) drugs. Accumulation of these drugs in the transgenic lines was much more rapid. T. congolense is also inherently less sensitive to suramin than T. brucei, despite accumulating it faster. Expression of a proposed suramin transporter, located in T. brucei lysosomes, in T. congolense, did not alter its suramin sensitivity. We conclude that for several of the most important classes of trypanocides the presence of specific transporters, rather than drug targets, is the determining factor of drug efficacy.


Assuntos
Arsenicais , Tripanossomicidas , Trypanosoma congolense , Trypanosoma , Animais , Proteínas de Membrana Transportadoras , Pentamidina/metabolismo , Pentamidina/farmacologia , Suramina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/metabolismo
12.
Chem Biol Drug Des ; 99(6): 908-922, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35353953

RESUMO

Trypanosoma congolense is a pathogenic African animal trypanosome species causing devastating conditions leading to death of an infected host. The drawbacks of the existing trypanocidal drugs have led to the search for new drug candidates. In this study, ß-ionone at 15 and 30 mg/kg body weight (BW) was orally administered to T. congolense infected rats for 14 days followed by an assessment of anemia, organ damages, and the expression of T. congolense trans-sialidase gene variants. A significant decrease in parasitemia (p < .05) was observed in the animals treated with 15 mg/kg BW ß-ionone besides increased animal survival rate. A trypanosome-induced decrease in packed cell volume (PCV) and histopathological changes across tissues was significantly (p < .05) ameliorated following treatment with both doses of ß-ionone. This is in addition to reversing the parasite-induced upsurge in free serum sialic acid (FSA) and expression of T. congolense trans-sialidase gene variants (TconTS1, TconTS3, and TconTS4). Correlation analysis revealed a positive correlation (p > .05) between FSA with the TconTS gene expressions. In addition, the compound inhibited partially purified T. congolense sialidase and phospholipase A2 via mixed inhibition pattern with inhibition binding constants of 25.325 and 4.550 µM, respectively, while molecular docking predicted binding energies of -5.6 kcal/mol for both enzymes. In conclusion, treatment with ß-ionone suppressed T. congolense proliferation and protected the animals against some of the parasite-induced pathologies whilst the effect on anemia development might be due to inhibition of sialidase and PLA2 activities as well as the expression levels of TconTS3 and TconTS4.


Assuntos
Anemia , Norisoprenoides , Trypanosoma congolense , Tripanossomíase Africana , Anemia/tratamento farmacológico , Anemia/parasitologia , Animais , Proliferação de Células , Expressão Gênica , Glicoproteínas , Simulação de Acoplamento Molecular , Neuraminidase , Norisoprenoides/farmacologia , Fosfolipases A2/genética , Ratos , Trypanosoma congolense/genética , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
13.
Parasit Vectors ; 15(1): 64, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35183235

RESUMO

This review focuses on the most reliable and up-to-date methods for diagnosing trypanosomoses, a group of diseases of wild and domestic mammals, caused by trypanosomes, parasitic zooflagellate protozoans mainly transmitted by insects. In Africa, the Americas and Asia, these diseases, which in some cases affect humans, result in significant illness in animals and cause major economic losses in livestock. A number of pathogens are described in this review, including several Salivarian trypanosomes, such as Trypanosoma brucei sspp. (among which are the agents of sleeping sickness, the human African trypanosomiasis [HAT]), Trypanosoma congolense and Trypanosoma vivax (causing "Nagana" or animal African trypanosomosis [AAT]), Trypanosoma evansi ("Surra") and Trypanosoma equiperdum ("Dourine"), and Trypanosoma cruzi, a Stercorarian trypanosome, etiological agent of the American trypanosomiasis (Chagas disease). Diagnostic methods for detecting zoonotic trypanosomes causing Chagas disease and HAT in animals, as well as a diagnostic method for detecting animal trypanosomes in humans (the so-called "atypical human infections by animal trypanosomes" [a-HT]), including T. evansi and Trypanosoma lewisi (a rat parasite), are also reviewed. Our goal is to present an integrated view of the various diagnostic methods and techniques, including those for: (i) parasite detection; (ii) DNA detection; and (iii) antibody detection. The discussion covers various other factors that need to be considered, such as the sensitivity and specificity of the various diagnostic methods, critical cross-reactions that may be expected among Trypanosomatidae, additional complementary information, such as clinical observations and epizootiological context, scale of study and logistic and cost constraints. The suitability of examining multiple specimens and samples using several techniques is discussed, as well as risks to technicians, in the context of specific geographical regions and settings. This overview also addresses the challenge of diagnosing mixed infections with different Trypanosoma species and/or kinetoplastid parasites. Improving and strengthening procedures for diagnosing animal trypanosomoses throughout the world will result in a better control of infections and will significantly impact on "One Health," by advancing and preserving animal, human and environmental health.


Assuntos
Mal do Coito (Veterinária) , Trypanosoma congolense , Trypanosoma , Tripanossomíase Africana , Tripanossomíase , Animais , Ratos , Trypanosoma/genética , Trypanosoma congolense/genética , Trypanosoma vivax/genética , Tripanossomíase/diagnóstico , Tripanossomíase/epidemiologia , Tripanossomíase/veterinária , Tripanossomíase Africana/parasitologia
14.
PLoS Negl Trop Dis ; 16(2): e0009585, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35130274

RESUMO

Trans-sialidases (TS) represent a multi-gene family of unusual enzymes, which catalyse the transfer of terminal sialic acids (Sia) from sialoglycoconjugates to terminal galactose or N-acetylgalactosamine residues of oligosaccharides without the requirement of CMP-Neu5Ac, the activated Sia used by typical sialyltransferases. Enzymes comprise a N-terminal catalytic domain (CD) followed by a lectin-like domain (LD). Most work on trypanosomal TS has been done on enzymatic activities focusing on the CD of TS from Trypanosoma cruzi (causing Chagas disease in Latin America), subspecies of Trypanosoma brucei, (causing human sleeping sickness in Africa) and Trypanosoma congolense (causing African Animal Trypanosomosis in livestock). Previously, we demonstrated that T. congolense TS (TconTS)-LD binds to several carbohydrates, such as 1,4-ß-mannotriose. In this study we investigated the influence of TconTS3-LD on Sia transfer efficiency of TconTS1a-CD by swapping domains. in silico analysis on structure models of TconTS enzymes revealed the potential of domain swaps between TconTS1a and TconTS3 without structural disruptions of the enzymes overall topologies. Recombinant domain swapped TconTS1a/TS3 showed clear Sia transfer activity, when using fetuin and lactose as Sia donor and acceptor substrates, respectively. While Sia transfer activity remained unchanged from the level of TconTS1a, hydrolytic release of free Neu5Ac as a side product was suppressed resulting in increased transfer efficiency. Presence of 1,4-ß-mannotriose during TS reactions modulates enzyme activities enhancing transfer efficiency possibly due to occupation of the binding site in TconTS1a-LD. Interestingly this effect was in the same range as that observed when swapping TconTS1a-CD and TconTS3-LD. In summary, this study demonstrate the proof-of-principle for swapping CDs and LDs of TconTS and that TconTS3-LD influences enzymatic activity of TconTS1a-CD providing evidence that LDs play pivotal roles in modulating activities and biological functions of TconTS and possibly other TS.


Assuntos
Glicoproteínas/química , Glicoproteínas/metabolismo , Neuraminidase/química , Neuraminidase/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Trypanosoma congolense/enzimologia , Acetilgalactosamina/metabolismo , Sítios de Ligação , Catálise , Galactose/metabolismo , Glicoproteínas/genética , Neuraminidase/genética , Oligossacarídeos/metabolismo , Proteínas de Protozoários/genética , Ácidos Siálicos/metabolismo , Trypanosoma congolense/química , Trypanosoma congolense/genética
15.
Molecules ; 27(2)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35056785

RESUMO

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of -4.9 and -5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (-67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (-77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.


Assuntos
Floroglucinol/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Anemia/complicações , Anemia/tratamento farmacológico , Animais , Feminino , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Tamanho do Órgão/efeitos dos fármacos , Floroglucinol/química , Floroglucinol/uso terapêutico , Fosfolipases A2/química , Fosfolipases A2/metabolismo , Ratos Wistar , Análise de Sobrevida , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/parasitologia , Tripanossomíase Africana/sangue , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia
16.
Acta Parasitol ; 67(1): 120-129, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34156634

RESUMO

INTRODUCTION: Trypanosomiasis is a neglected disease of humans and livestock caused by single-celled flagellated haemo-protozoan parasites belonging to the genus Trypanosoma. PURPOSE: Widespread resistance to trypanocidal drugs creates urgent need for new, more effective drugs with potential to inhibit important trypanosome molecular targets. METHODS: Nine column chromatographic, partially purified leaf fractions of Azadirachta indica (AIF) were subjected to trypanosome alternative oxidase (TAO) inhibition assay using ubiquinol oxidase assay. The potent TAO inhibitors were evaluated for trypanocidal activities against T. congolense in rat model using in vitro, ex vivo, and in vivo assays. Complete cessation or reduction in parasite motility was scored from 0 (no parasite) to 6 (greater than or equal to 6 × 107 trypanosomes/milliliter of blood), and was used to evaluate the efficacy of in vitro treatments. RESULTS: Only AIF1, AIF2, and AIF5 significantly inhibited TAO. AIF1 and AIF5 produced significant, dose-dependent suppression of parasite motility reaching score zero within 1 h with EC50 of 0.005 and 0.004 µg/µL, respectively, while trypanosome-laden blood was still at score six with an EC50 of 44,086 µg/µL. Mice inoculated with the concentrations at scores 0 and 1 (1-2 moribund parasites) at the end of the experiment did not develop parasitaemia. The two fractions significantly (p < 0.05) lowered parasite burden, with the AIF5 exhibiting highest in vivo trypanocidal effects. Packed cell volume was significantly higher in AIF1 (p < 0.05) and AIF5 (p < 0.001) groups compared to DMSO-treated group. Only AIF5 significantly (p < 0.05) lowered malondialdehyde. CONCLUSION: AIF1 and AIF5 offer prospects for the discovery of TAO inhibitor(s).


Assuntos
Azadirachta , Trypanosoma congolense , Tripanossomíase Africana , Animais , Camundongos , Proteínas Mitocondriais , Oxirredutases , Folhas de Planta , Proteínas de Plantas , Ratos , Tripanossomíase Africana/tratamento farmacológico
17.
Parasitol Res ; 121(1): 423-431, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34746978

RESUMO

African animal trypanosomosis is an important wasting and endemic protozoan disease causing morbidities and mortalities in animals in the sub-Saharan Africa. Currently, chemotherapy is the widely used method of African animal trypanosomosis control, especially in dogs in the sub-Saharan Africa. However, their efficacy is threatened by the emergence of drug-resistant trypanosomes owing to their extensive use and misuse over several decades amongst other factors. Thus, this study focused on the trypanocidal sensitivity and characterization of Trypanosoma species isolated from dogs in Enugu North Senatorial Zone (ENSZ), Southeastern Nigeria. Trypanosoma brucei (n = 44) and T. congolense (n = 4) isolated from naturally infected dogs in ENSZ, Southeastern Nigeria, between January and August 2016 were subjected to single dose test to assess their sensitivity to diminazene aceturate (DA) and isometamidium chloride (ISM). Subsequently, DA and multidrug-resistant isolates were further subjected to DA multi-dose test and CD50 was determined and was used to characterize the drug-resistant trypanosomes. Clones were derived from a randomly selected multidrug-resistant isolate and their sensitivity also assessed. 100% and 83.3% of T. congolense and T. brucei respectively were resistant to the trypanocides. Amongst the drug-resistant isolates, 50%, 16.7%, and 33.3% were resistant to DA, ISM, and both trypanocides respectively with CD50 ranging between 11 and 32.34 mg/kg. Drug-resistant trypanosomes were characterized into highly resistant (CD50 = 11-24.99 mg/kg) and very highly resistant (CD50 = > 25 mg/kg) trypanosome isolates. Clones also expressed high levels of resistance to both DA and ISM with CD50 values between 35.58 and 38.85 mg/kg. Trypanocidal resistance was, thus, confirmed and appears to be widespread in dogs in ENSZ, Southeastern Nigeria. The adoption of an integrated trypanosomosis control strategy in ENSZ is most desirous.


Assuntos
Preparações Farmacêuticas , Tripanossomicidas , Trypanosoma congolense , Tripanossomíase Africana , Animais , Diminazena , Cães , Resistência a Medicamentos , Nigéria , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico
18.
PLoS Negl Trop Dis ; 15(12): e0010036, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34937054

RESUMO

BACKGROUND: The existence of an animal reservoir of Trypanosoma brucei gambiense (T. b. gambiense), the agent of human African trypanosomiasis (HAT), may compromise the interruption of transmission targeted by World Health Organization. The aim of this study was to investigate the presence of trypanosomes in pigs and people in the Vavoua HAT historical focus where cases were still diagnosed in the early 2010's. METHODS: For the human survey, we used the CATT, mini-anion exchange centrifugation technique and immune trypanolysis tests. For the animal survey, the buffy coat technique was also used as well as the PCR using Trypanosoma species specific, including the T. b. gambiense TgsGP detection using single round and nested PCRs, performed from animal blood samples and from strains isolated from subjects positive for parasitological investigations. RESULTS: No HAT cases were detected among 345 people tested. A total of 167 pigs were investigated. Free-ranging pigs appeared significantly more infected than pigs in pen. Over 70% of free-ranging pigs were positive for CATT and parasitological investigations and 27-43% were positive to trypanolysis depending on the antigen used. T. brucei was the most prevalent species (57%) followed by T. congolense (24%). Blood sample extracted DNA of T. brucei positive subjects were negative to single round TgsGP PCR. However, 1/22 and 6/22 isolated strains were positive with single round and nested TgsGP PCRs, respectively. DISCUSSION: Free-ranging pigs were identified as a multi-reservoir of T. brucei and/or T. congolense with mixed infections of different strains. This trypanosome diversity hinders the easy and direct detection of T. b. gambiense. We highlight the lack of tools to prove or exclude with certainty the presence of T. b. gambiense. This study once more highlights the need of technical improvements to explore the role of animals in the epidemiology of HAT.


Assuntos
Reservatórios de Doenças/parasitologia , Doenças dos Suínos/parasitologia , Trypanosoma brucei gambiense/isolamento & purificação , Trypanosoma congolense/isolamento & purificação , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária , Animais , Animais Domésticos/parasitologia , Costa do Marfim/epidemiologia , Humanos , Reação em Cadeia da Polimerase , Suínos , Doenças dos Suínos/epidemiologia , Trypanosoma brucei gambiense/genética , Trypanosoma brucei gambiense/fisiologia , Trypanosoma congolense/genética , Trypanosoma congolense/fisiologia , Tripanossomíase Africana/epidemiologia
19.
BMC Complement Med Ther ; 21(1): 290, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34837971

RESUMO

BACKGROUND: Trypanosomiasis is one of the neglected tropical diseases of both humans and animals which decreases their productivity and causes death in the worst scenario. Unavailability of vaccines, the low therapeutic index of trypanocidal drugs, and the development of resistance lead to the need for research focused on developing alternative treatment options especially from medicinal plants. The present study was aimed to investigate antitrypanosomal activities of leaves of Cymbopogon citratus and seeds of Lepidium sativum in in-vivo mice model. METHODS: The plant extracts were prepared by maceration using 80% methanol and reconstituted with 10% dimethyl sulfoxide (DMSO) to have the desired concentration. The test doses were adjusted to 100, 200 and 400 mg/kg based on the toxicity profile. The plants extracts were administered to the respective groups of mice after the 12th day of field isolate T. congolense inoculation for seven consecutive days. The level of parasitemia, bodyweight, packed cell volume (PCV), and differential white blood cell counts were measured. RESULTS: The in -vivo test results revealed that both plant extracts had dose-dependent antitrypanosomal activity. Both crude extracts showed a significant reduction in parasite load (P < 0.05), increased or prevent the fall of PCV value (P < 0.05), decreased lymphocytosis and increased neutrophil counts (p < 0.05) and improved bodyweight but significant bodyweight increment (P < 0.05) was observed only in C. citratus treated mice compared to the negative and positive controls. CONCLUSION: The present study concluded that the crude extracts of leaves of C. citratus and seeds of L. sativum had antitrypanosomal effects. Both plants extracts reduced parasitemia level, prevented anemia and improved bodyweight of treated mice. Comparative results from all tested parameters showed that the best activities were observed with C. citratus treated groups of mice.


Assuntos
Extratos Vegetais/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/efeitos dos fármacos , Animais , Cymbopogon , Etiópia , Feminino , Lepidium sativum , Masculino , Camundongos , Parasitemia/tratamento farmacológico , Folhas de Planta , Sementes
20.
Prev Vet Med ; 197: 105507, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34673473

RESUMO

Trypanosomosis is a major cause of morbidity and mortality in working equids in The Gambia. Recently, a progressive, severe neurological syndrome characterised by a diffuse lymphoplasmacytic meningoencephalitis has been identified and associated with Trypanosoma brucei infection of the central nervous system. The pathogenesis of cerebral trypanosomosis is unclear and the clinical syndrome not well described. This observational cross-sectional study aimed to identify host and parasite related risk factors associated with the development of cerebral trypanosomosis and to describe the neurological syndrome associated with cerebral trypanosomosis. History, signalment, clinical and laboratory parameters were collected from 326 horses and donkeys presented to The Gambia Horse and Donkey Trust. Neurological derangements in affected animals were described. Species-specific polymerase chain reaction (PCR) for Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei was performed. The associations between signalment, clinical and laboratory parameters and PCR results were assessed using multivariable logistic regression. The overall prevalence of trypanosomosis was 50 %, with infections dominated by T. congolense (44.1 %) and a lower intensity of T. brucei (7.4 %) and T. vivax (6.5 %). Overall, 54.8 % of neurological cases were PCR positive for trypanosomosis. Within the neurological sub-population prevalence remained similar to the whole population for T. congolense (48.4 %) and T. vivax (6.5 %); whilst the prevalence increased markedly for T. brucei (32.3 %). Co-infections were identified in 32.3 % of neurological cases. Donkeys typically presented with progressive cerebral dysfunction and cranial nerve deficits, whereas in horses a progressive spinal ataxia was predominant. Mortality in affected animals was high (82.4 %). The final multivariable model identified a significant association between body condition score ≤2 (OR 11.4; 95 % CI 4.6-27.9; P = <0.001), and T. congolense and T. brucei. coinfection (OR 20.6; 95 % CI 1.71-244.1; P = 0.016) with the presence of neurological deficits. This study has provided clinically relevant information confirming the link between T. brucei and neurological disease outbreak in the equid population of The Gambia, and crucially identified co-infection with T. brucei and T. congolense as a major risk factor for the development of neurological trypanosomosis. Further research is required to identify the epidemiology of co-infection in equidae of The Gambia, so that cerebral trypanosomosis can be better prevented in this vulnerable population.


Assuntos
Coinfecção , Doenças dos Cavalos , Trypanosoma brucei brucei , Trypanosoma congolense , Trypanosoma , Tripanossomíase Africana , Animais , Coinfecção/epidemiologia , Coinfecção/veterinária , Gâmbia/epidemiologia , Cavalos , Fatores de Risco , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária
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