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The American Journal of Tropical... Jun 2024Animal African trypanosomiasis, also known as nagana, is caused by Trypanosoma species, which cause significant clinical diseases and lead to losses in animal...
Animal African trypanosomiasis, also known as nagana, is caused by Trypanosoma species, which cause significant clinical diseases and lead to losses in animal production. We carried out a cross-sectional survey to investigate the composition of vectors and parasite diversity in two districts in the eastern region of Ghana where pigs and cattle were exposed to tsetse bites. We performed cytochrome c oxidase subunit 1 polymerase chain reaction (PCR) to identify tsetse species and internal transcribed spacer 1 PCR to identify Trypanosoma species. Also, we investigated the source of tsetse blood meal based on mitochondrial cytochrome b gene sequence analysis. A total of 229 tsetse, 65 pigs, and 20 cattle were investigated for trypanosomes. An overall vector density of 4.3 tsetse/trap/day was observed. A trypanosome prevalence of 58.9% (95% CI = 52.5-65.1%), 46.2% (95% CI = 34.6-58.1%), and 0.0% (95% CI = 0.0-16.1%) in tsetse, pigs, and cattle, respectively, was detected. Trypanosoma congolense was predominant, with a prevalence of 33.3% (95% CI = 73.3-86.5%) in tsetse. There was evidence of multiple infections in tsetse and pigs. Approximately 39% of the tsetse were positive for multiple infections of T. congolense and Trypanosoma simiae. Parasite prevalence in pigs across the communities was high, with significant differences associated between locations (χ2 = 28.06, 95% CI = 0.05-0.81, P = 0.0009). Tsetse blood meal analysis revealed feeding on domestic Sus scrofa domesticus (pigs) and Phacochoerus africanus (warthogs). Infective tsetse may transmit trypanosomes to livestock and humans in the communities studied.
Topics: Animals; Ghana; Tsetse Flies; Cattle; Trypanosomiasis, African; Swine; Trypanosoma; Cross-Sectional Studies; Swine Diseases; Insect Vectors; Forests; Cattle Diseases; Prevalence; Female
PubMed: 38697074
DOI: 10.4269/ajtmh.23-0329 -
Fitoterapia Jul 2024Anogeissus leiocarpus (DC.) Guill. & Perr. belongs to the family Combretaceae and is used both by African traditional medical practitioners and livestock rearers to... (Review)
Review
Anogeissus leiocarpus (DC.) Guill. & Perr. belongs to the family Combretaceae and is used both by African traditional medical practitioners and livestock rearers to treat diseases such as African trypanosomiasis, animal diarrhoea, asthma, cancer, cough, diabetes, dysentery, erectile dysfunction, fever, giardiasis, helminthiases, meningitis, menstrual disorders, monkeypox, oral infections, poliomyelitis, sickle cell anaemia, snake bites, toothache, urinary schistosomiasis, and yellow fever. Some of these activities have been associated with the presence of polyphenols in the plant which include ellagic acid derivatives, flavonoids, stilbenes, tannins, and triterpenes. Several bioactive molecules have been identified from A. leiocarpus. These include the main active constituents, ellagitannins, ellagic acid derivates, flavonoids and triterpenes. Pharmacological studies have confirmed its antibacterial, antifungal, antihyperglycemic, antihypertensive, antimalarial, antioxidative, antiparasitic, antitumour and anti-ulcer effects. The stem bark has been investigated mainly for biological activities and phytochemistry, and it is the most mentioned plant part highlighted by the traditional users in ethnomedicinal surveys. In vitro and in vivo models, which revealed a wide range of pharmacological actions against parasites causing helminthiasis, leishmaniasis, malaria and trypanosomiasis, have been used to study compounds from A. leiocarpus. Because of its uses in African traditional medicine and veterinary practices, A. leiocarpus has received considerable attention from researchers. The current review provides a comprehensive overview and critical appraisal of scientific reports on A. leiocarpus, covering its traditional uses, pharmacological activities and phytochemistry.
Topics: Phytochemicals; Medicine, African Traditional; Combretaceae; Humans; Plant Extracts; Animals; Plant Bark
PubMed: 38692415
DOI: 10.1016/j.fitote.2024.105979 -
PLoS Neglected Tropical Diseases May 2024
Topics: Humans; Trypanosomiasis, African; Disease Eradication; Animals; Africa; Neglected Diseases
PubMed: 38691551
DOI: 10.1371/journal.pntd.0012091 -
International Journal of Molecular... Apr 2024In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African...
In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of and , are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively. Therefore, in our study we identified a novel lead-like compound, i.e., inhibitor , which we proved to be active against both targets, with a = 5.06 µM towards rhodesain and an IC = 40.43 µM against falcipain-2.
Topics: Humans; Antimalarials; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Malaria; Nitriles; Plasmodium falciparum; Protozoan Proteins; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 38673995
DOI: 10.3390/ijms25084410 -
International Journal of Molecular... Apr 2024Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite . There is currently a lack of effective and...
Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite . There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. glucokinase (GlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of GlcK inhibitors that also exhibited anti- efficacy called the 3-nitro-2-phenyl-2-chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited GlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds and were determined to inhibit GlcK quite well with IC values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2-chromene analogues, two of which were and (compounds and , respectively). Twelve of these compounds had a one-point change from the chemical structure of . The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the GlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC determinations, and an assessment of structure-activity relationships. Our results reveal that the 3-nitro-2-phenyl--chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.
Topics: Animals; Humans; Mice; Benzopyrans; Chagas Disease; Drug Discovery; Enzyme Inhibitors; Glucokinase; High-Throughput Screening Assays; Molecular Docking Simulation; NIH 3T3 Cells; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Protein Kinase Inhibitors
PubMed: 38673904
DOI: 10.3390/ijms25084319 -
Clinical Infectious Diseases : An... Apr 2024Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden,...
BACKGROUND
Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals.
METHODS
We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases.
RESULTS
We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission.
CONCLUSIONS
Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease.
Topics: Humans; Neglected Diseases; Chagas Disease; Asymptomatic Infections; Leishmaniasis, Visceral; Models, Theoretical; Trypanosomiasis, African; India; Animals
PubMed: 38662705
DOI: 10.1093/cid/ciae096 -
Clinical Infectious Diseases : An... Apr 2024Great progress is being made toward the goal of elimination as a public health problem for neglected tropical diseases such as leprosy, human African trypanosomiasis,...
BACKGROUND
Great progress is being made toward the goal of elimination as a public health problem for neglected tropical diseases such as leprosy, human African trypanosomiasis, Buruli ulcer, and visceral leishmaniasis, which relies on intensified disease management and case finding. However, strategies for maintaining this goal are still under discussion. Passive surveillance is a core pillar of a long-term, sustainable surveillance program.
METHODS
We use a generic model of disease transmission with slow epidemic growth rates and cases detected through severe symptoms and passive detection to evaluate under what circumstances passive detection alone can keep transmission under control.
RESULTS
Reducing the period of infectiousness due to decreasing time to treatment has a small effect on reducing transmission. Therefore, to prevent resurgence, passive surveillance needs to be very efficient. For some diseases, the treatment time and level of passive detection needed to prevent resurgence is unlikely to be obtainable.
CONCLUSIONS
The success of a passive surveillance program crucially depends on what proportion of cases are detected, how much of their infectious period is reduced, and the underlying reproduction number of the disease. Modeling suggests that relying on passive detection alone is unlikely to be enough to maintain elimination goals.
Topics: Humans; Neglected Diseases; Disease Eradication; Public Health; Tropical Medicine; Population Surveillance
PubMed: 38662695
DOI: 10.1093/cid/ciae097 -
PLoS Pathogens Apr 2024In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role...
In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role is fulfilled by a dense, glycosylated protein layer composed of variant surface glycoproteins (VSGs), which undergo antigenic variation and provide a physical barrier that shields the underlying invariant surface glycoproteins (ISGs). The protective shield's limited permeability comes at the cost of restricted access to the extracellular host environment, raising questions regarding the specific function of the ISG repertoire. In this study, we employ an integrative structural biology approach to show that intrinsically disordered membrane-proximal regions are a common feature of members of the ISG super-family, conferring the ability to switch between compact and elongated conformers. While the folded, membrane-distal ectodomain is buried within the VSG layer for compact conformers, their elongated counterparts would enable the extension beyond it. This dynamic behavior enables ISGs to maintain a low immunogenic footprint while still allowing them to engage with the host environment when necessary. Our findings add further evidence to a dynamic molecular organization of trypanosome surface antigens wherein intrinsic disorder underpins the characteristics of a highly flexible ISG proteome to circumvent the constraints imposed by the VSG coat.
Topics: Variant Surface Glycoproteins, Trypanosoma; Trypanosomiasis, African; Protozoan Proteins; Humans; Membrane Glycoproteins; Animals
PubMed: 38648216
DOI: 10.1371/journal.ppat.1012186 -
PLoS Pathogens Apr 2024Trypanosoma brucei are protozoan parasites that cause sleeping sickness in humans and nagana in cattle. Inside the mammalian host, a quorum sensing-like mechanism...
Trypanosoma brucei are protozoan parasites that cause sleeping sickness in humans and nagana in cattle. Inside the mammalian host, a quorum sensing-like mechanism coordinates its differentiation from a slender replicative form into a quiescent stumpy form, limiting growth and activating metabolic pathways that are beneficial to the parasite in the insect host. The post-translational modification of proteins with the Small Ubiquitin-like MOdifier (SUMO) enables dynamic regulation of cellular metabolism. SUMO can be conjugated to its targets as a monomer but can also form oligomeric chains. Here, we have investigated the role of SUMO chains in T. brucei by abolishing the ability of SUMO to polymerize. We have found that parasites able to conjugate only SUMO monomers are primed for differentiation. This was demonstrated for monomorphic lines that are normally unable to produce stumpy forms in response to quorum sensing signaling in mice, and also for pleomorphic cell lines in which stumpy cells were observed at unusually low parasitemia levels. SUMO chain mutants showed a stumpy compatible transcriptional profile and better competence to differentiate into procyclics. Our study indicates that SUMO depolymerization may represent a coordinated signal triggered during stumpy activation program.
Topics: Animals; Trypanosoma brucei brucei; Mice; Trypanosomiasis, African; Cell Differentiation; Small Ubiquitin-Related Modifier Proteins; Protozoan Proteins; Protein Processing, Post-Translational; Quorum Sensing; Humans; Sumoylation
PubMed: 38635823
DOI: 10.1371/journal.ppat.1012166 -
PLoS Neglected Tropical Diseases Apr 2024The insecticide-treated baits known as Tiny Targets are one of the cheapest means of controlling riverine species of tsetse flies, the vectors of the trypanosomes that...
BACKGROUND
The insecticide-treated baits known as Tiny Targets are one of the cheapest means of controlling riverine species of tsetse flies, the vectors of the trypanosomes that cause sleeping sickness in humans. Models of the efficacy of these targets deployed near rivers are potentially useful in planning control campaigns and highlighting the principles involved.
METHODS AND PRINCIPAL FINDINGS
To evaluate the potential of models, we produced a simple non-seasonal model of the births, deaths, mobility and aging of tsetse, and we programmed it to simulate the impact of seven years of target use against the tsetse, Glossina fuscipes fuscipes, in the riverine habitats of NW Uganda. Particular attention was given to demonstrating that the model could explain three matters of interest: (i) good control can be achieved despite the degradation of targets, (ii) local elimination of tsetse is impossible if invasion sources are not tackled, and (iii) with invasion and target degradation it is difficult to detect any effect of control on the age structure of the tsetse population.
CONCLUSIONS
Despite its simplifications, the model can assist planning and teaching, but allowance should be made for any complications due to seasonality and management challenges associated with greater scale.
Topics: Tsetse Flies; Animals; Insect Control; Uganda; Insecticides; Humans; Trypanosomiasis, African; Insect Vectors
PubMed: 38626189
DOI: 10.1371/journal.pntd.0011578