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Concept: Trypanosomiasis

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BACKGROUND: Trypanosomosis, a protozoal disease affecting livestock, transmitted by Glossina (tsetse) flies is a major constraint to agricultural production in Sub-Saharan Africa. It is accepted that utilization of the native trypanotolerance exhibited in some of the African cattle breeds to improve trypanotolerance of more productive but susceptible breeds, will offer a cost effective and sustainable solution to the problem. The success of this approach is based on the premise that quantitative trait loci previously identified under relatively controlled situations confer useful trypanotolerance under natural field situations. As part of a study to authenticate this hypothesis, a population of 192 cattle, consisting of six batches of N'Dama and Kenya-Boran backcross animals [(N'Dama x Kenya-Boran) x Kenya-Boran] born over the period 2002 to 2006 was constructed. Some of the batches also included pure Kenya-Boran cattle, or N'Dama x Kenya- Boran F1 animals. Each batch was exposed as yearlings to natural field trypanosomosis challenge over a period of about one year; the entire challenge period extending from December 2003 to June 2007. Performance of the animals was evaluated by weekly or biweekly measurements of body weight, packed blood cell volume (PCV), parasitemia score, and number of trypanocide treatments. From these basic data, 49 phenotypes were constructed reflecting dynamics of body weight, packed cell volume (PCV) and parasitemia under challenge. RESULTS: Females were distinctly more trypanotolerant than males. F1, backcross and pure Kenya- Boran animals ranked in that order with respect to trypanotolerance. Overall batch effects were highly significant (p<0.001) for most traits, and were generally more significant than the gender or genetic type effects. The superior trypanotolerance of the F1 animals was expressed in all three components of animal defense strategies against pathogens: Avoidance resistance, and tolerance. CONCLUSIONS: The results show that trypanotolerance derived from the N'Dama is expressed under field conditions; and that the trait is primarily additive in nature, being expressed in heterozygous condition and in a three-quarters Boran genetic background. The results further, underscore the complexity of the trait in the field manifesting all three host disease-control strategies, and show the importance of gender and local environmental conditions in determining response to challenge.

Concepts: Genetics, Male, Effect, Quantitative trait locus, African trypanosomiasis, Tsetse fly, Mean corpuscular volume, Trypanosomiasis

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African trypanosomes are unicellular flagellated parasites causing trypanosomiases in Africa, a group of severe diseases also known as sleeping sickness in human and nagana in cattle. These parasites are almost exclusively transmitted by the bite of the tsetse fly. In this review, we describe and compare the three developmental programs of the main trypanosome species impacting human and animal health, with focus on the most recent observations. From here, some reflections are made on research issues concerning trypanosome developmental biology in the tsetse fly that are to be addressed in the future.

Concepts: Human, Africa, Species, African trypanosomiasis, Tsetse fly, Sleeping sickness, Trypanosomiasis, Animal trypanosomiasis

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For the first time, differential attraction of pathogen vectors to vertebrate animals is investigated for novel repellents which when applied to preferred host animals turn them into non-hosts thereby providing a new paradigm for innovative vector control. For effectively controlling tsetse flies (Glossina spp.), vectors of African trypanosomosis, causing nagana, repellents more powerful than plant derived, from a non-host animal the waterbuck, Kobus ellipsiprymnus defassa, have recently been identified. Here we investigate these repellents in the field to protect cattle from nagana by making cattle as unattractive as the buck.

Concepts: African trypanosomiasis, Tsetse fly, East Africa, Host, Hippoboscoidea, Sterile insect technique, Trypanosomiasis, Animal trypanosomiasis

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Trypanosoma brucei, the causative agent of African sleeping sickness, is transmitted to its mammalian host by the tsetse. In the fly, the parasite’s surface is covered with invariant procyclin, while in the mammal it resides extracellularly in its bloodstream form (BF) and is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). In the BF, the parasite varies this highly immunogenic surface VSG using a repertoire of ~2500 distinct VSG genes. Recent reports in mammalian systems point to a role for histone acetyl-lysine recognizing bromodomain proteins in the maintenance of stem cell fate, leading us to hypothesize that bromodomain proteins may maintain the BF cell fate in trypanosomes. Using small-molecule inhibitors and genetic mutants for individual bromodomain proteins, we performed RNA-seq experiments that revealed changes in the transcriptome similar to those seen in cells differentiating from the BF to the insect stage. This was recapitulated at the protein level by the appearance of insect-stage proteins on the cell surface. Furthermore, bromodomain inhibition disrupts two major BF-specific immune evasion mechanisms that trypanosomes harness to evade mammalian host antibody responses. First, monoallelic expression of the antigenically varied VSG is disrupted. Second, rapid internalization of antibodies bound to VSG on the surface of the trypanosome is blocked. Thus, our studies reveal a role for trypanosome bromodomain proteins in maintaining bloodstream stage identity and immune evasion. Importantly, bromodomain inhibition leads to a decrease in virulence in a mouse model of infection, establishing these proteins as potential therapeutic drug targets for trypanosomiasis. Our 1.25Å resolution crystal structure of a trypanosome bromodomain in complex with I-BET151 reveals a novel binding mode of the inhibitor, which serves as a promising starting point for rational drug design.

Concepts: Immune system, Antibody, Protein, Gene, Enzyme inhibitor, Trypanosoma brucei, African trypanosomiasis, Trypanosomiasis

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The highly motile and versatile protozoan pathogen Trypanosoma brucei undergoes a complex life cycle in the tsetse fly. Here we introduce the host insect as an expedient model environment for microswimmer research, as it allows examination of microbial motion within a diversified, secluded and yet microscopically tractable space. During their week-long journey through the different microenvironments of the fly´s interior organs, the incessantly swimming trypanosomes cross various barriers and confined surroundings, with concurrently occurring major changes of parasite cell architecture. Multicolour light sheet fluorescence microscopy provided information about tsetse tissue topology with unprecedented resolution and allowed the first 3D analysis of the infection process. High-speed fluorescence microscopy illuminated the versatile behaviour of trypanosome developmental stages, ranging from solitary motion and near-wall swimming to collective motility in synchronised swarms and in confinement. We correlate the microenvironments and trypanosome morphologies to high-speed motility data, which paves the way for cross-disciplinary microswimmer research in a naturally evolved environment.

Concepts: Immune system, Bacteria, Biology, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Microscopy, Trypanosomiasis

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Changes in agricultural practices and the resulting extinction of wildlife have led to the reduction or disappearance of savannah tsetse species. Riparian tsetse such as Glossina palpalis gambiensis Vanderplank 1949 and Glossina tachinoides Westwood 1850 (Diptera: Glossinidae) continue to persist in peridomestic sites, transmitting trypanosomiasis. At present, little is known about interspecies differences in feeding behaviour in these two species in southeast Mali, or of the phenomenon of multiple bloodmeals. To study these topics, 279 samples of G. p. gambiensis and G. tachinoides containing host DNA, caught in the Sikasso region between November 2008 and April 2009, were analysed by applying host species-specific primers and sequencing. Human accounted for > 66% of G. p. gambiensis bloodmeals, whereas G. tachinoides contained in equal parts DNA of human, cattle or both, showing a significantly higher proportion of multiple host use. Further, the trypanosome infection rate was found to be three-fold higher in G. tachinoides. Logistic regression analysis revealed double-feeding and infection to be independent of one another, but showed infection to be correlated with engorgement in G. p. gambiensis and female sex in G. tachinoides. Enhanced host-seeking activities paired with the high trypanosome infection rate found in G. tachinoides would indicate that this species has a higher vectorial capacity than G. p. gambiensis.

Concepts: Regression analysis, Logistic regression, African trypanosomiasis, Tsetse fly, Host, Hippoboscoidea, Sterile insect technique, Trypanosomiasis

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Trypanosoma brucei are extracellular kinetoplastid parasites transmitted by the bloodsucking tsetse fly. They are responsible for the fatal disease human African trypanosomiasis (HAT), also known as Sleeping Sickness. In late stage infection, trypanosomes cross the blood-brain barrier (BBB) and invade the central nervous system (CNS) invariably leading to coma and death if untreated. There is no available vaccine and current late stage HAT chemotherapy consists of either melarsoprol, which is highly toxic causing up to 8% of deaths, or nifurtimox-eflornithine combination therapy (NECT), which is costly and difficult to administer. There is therefore an urgent need to identify new late stage HAT drug candidates. Here we review how current imaging tools, ranging from fluorescent confocal microscopy of live immobilised cells in culture to whole animal imaging, are providing insight into T. brucei biology, parasite / host interplay, trypanosome CNS invasion and disease progression. We also consider how imaging tools can be used for candidate drug screening purposes that could lead to new chemotherapies. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Trypanosome, Tsetse fly, Trypanosomiasis

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BackgroundAfrican animal trypanosomiasis (AAT) is considered to be one of the greatest constraints to livestock production and livestock-crop integration in most African countries. South-eastern Uganda has suffered for more than two decades from outbreaks of zoonotic Human African Trypanosomiasis (HAT), adding to the burden faced by communities from AAT. There is insufficient AAT and HAT data available (in the animal reservoir) to guide and prioritize AAT control programs that has been generated using contemporary, sensitive and specific molecular techniques. This study was undertaken to evaluate the burden that AAT presents to the small-scale cattle production systems in south-eastern Uganda.MethodsRandomised cluster sampling was used to select 14% (57/401) of all cattle containing villages across Tororo District. Blood samples were taken from all cattle in the selected villages between September-December 2011; preserved on FTA cards and analysed for different trypanosomes using a suite of molecular techniques. Generalized estimating equation and Rogen-Gladen estimator models were used to calculate apparent and true prevalences of different trypanosomes while intra cluster correlations were estimated using a 1-way mixed effect analysis of variance (ANOVA) in R statistical software version 3.0.2.ResultsThe prevalence of all trypanosome species in cattle was 15.3% (95% CI; 12.2-19.1) while herd level trypanosome species prevalence varied greatly between 0-43%. Trypanosoma vivax (17.4%, 95% CI; 10.6-16.8) and Trypanosoma brucei rhodesiense (0.03%) were respectively, the most, and least prevalent trypanosome species identified.ConclusionsThe prevalence of bovine trypanosomes in this study indicates that AAT remains a significant constraint to livestock health and livestock production. There is need to implement tsetse and trypanosomiasis control efforts across Tororo District by employing effective, cheap and sustainable tsetse and trypanosomiasis control methods that could be integrated in the control of other endemic vector borne diseases like tick-borne diseases.

Concepts: Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Trypanosome, Tsetse fly, Sleeping sickness, Trypanosomiasis

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Tsetse flies (genus Glossina) are large blood-sucking dipteran flies that are important as vectors of human and animal trypanosomiasis in sub-Saharan Africa. Tsetse anatomy has been well described, including detailed accounts of the functional anatomy of the proboscis for piercing host skin and sucking up blood. The proboscis also serves as the developmental site for the infective metacyclic stages of several species of pathogenic livestock trypanosomes that are inoculated into the host with fly saliva. To understand the physical environment in which these trypanosomes develop, we have re-examined the microarchitecture of the tsetse proboscis.

Concepts: African trypanosomiasis, Flies, Tsetse fly, Hippoboscoidea, Trypanosomiasis

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The aim of this study was to evaluate the efficacy of 3'-deoxyadenosine and deoxycoformycin combination in the treatment of mice infected by T. cruzi, as well as to verify the influence of the treatment on purinergic enzymes. Heart and serum samples were collected from 60 mice (30 infected and 30 uninfected) at day 12 post-infection. To verify treatment efficacy, parasitemia was monitored, and the treatment with 3'-deoxy adenosine and deoxycoformycin combination was able to reduce it, but had no curative effect on mice. Seric activities of NTPDase (ATP and ADP substrate) and ADA were increased significantly in untreated mice infected by T. cruzi compared to the negative control, as well as mice treated with 3'-deoxyadenosine and deoxycoformycin (alone or combined) modulated the activity of NTPDase (ATP and ADP substrate), preventing them from increasing in infected animals (activity similar to healthy animals). Treatment with deoxycoformycin alone and associated with 3'-deoxyadenosine modulated the activity of ADA preventing them from increasing in infected animals. However, seric activities of ADA in mice treated with 3'-deoxyadenosine (cordycepin) alone does not modify the ADA activity compared with infected and non-treated mice. However, the 5'-nucleotidase activity decreased significantly in infected untreated animals and the same occurred with infected and treated animals deoxycoformycin and with 3'-deoxyadenosine. However, treatment with deoxycoformycin associated with 3'-deoxyadenosine preventing them from decreasing the 5'-nucleotidase activity. Therefore, we conclude that the treatments did not have curative success for mice infected by T. cruzi. However, the treatments were able to modulate the purinergic enzymes during the infection by T. cruzi, which may contribute to reduce the inflammatory damage in heart.

Concepts: Adenosine triphosphate, Enzyme, Chagas disease, Efficacy, Trypanosoma, Trypanosoma cruzi, Trypanosomiasis, Ada