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JAMA May 2024
Topics: Animals; Humans; Mice; Apolipoprotein L1; Kidney Diseases; Black or African American; United States; Renal Insufficiency, Chronic; Gene Frequency; Black People; Genetic Testing; Africa South of the Sahara; Caribbean Region; Central America; South America; Trypanosomiasis, African
PubMed: 38662391
DOI: 10.1001/jama.2024.2667 -
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 -
European Journal of Medicinal Chemistry May 2024Neglected tropical diseases (NTDs) comprise diverse infections with more incidence in tropical/sub-tropical areas. In spite of preventive and therapeutic achievements,... (Review)
Review
Neglected tropical diseases (NTDs) comprise diverse infections with more incidence in tropical/sub-tropical areas. In spite of preventive and therapeutic achievements, NTDs are yet serious threats to the public health. Epidemiological reports of world health organization (WHO) indicate that more than 1.5 billion people are afflicted with at least one NTD type. Among NTDs, leishmaniasis, chagas disease (CD) and human African trypanosomiasis (HAT) result in substantial morbidity and death, particularly within impoverished countries. The statistical facts call for robust efforts to manage the NTDs. Currently, most of the anti-NTD drugs are engaged with drug resistance, lack of efficient vaccines, limited spectrum of pharmacological effect and adverse reactions. To circumvent the issue, numerous scientific efforts have been directed to the synthesis and pharmacological development of chemical compounds as anti-infectious agents. A survey of the anti-NTD agents reveals that the majority of them possess privileged nitrogen, sulfur and oxygen-based heterocyclic structures. In this review, recent achievements in anti-infective small molecules against parasitic NTDs are described, particularly from the SAR (Structure activity relationship) perspective. We also explore current advocating strategies to extend the scope of anti-NTD agents.
Topics: Neglected Diseases; Humans; Structure-Activity Relationship; Molecular Structure; Small Molecule Libraries; Animals; Chagas Disease; Leishmaniasis; Antiprotozoal Agents; Parasitic Sensitivity Tests; Tropical Medicine
PubMed: 38643671
DOI: 10.1016/j.ejmech.2024.116396 -
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 -
PLoS Neglected Tropical Diseases Apr 2024Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the...
BACKGROUND
Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the 20th century. Sustained, coordinated efforts by different stakeholders working with national sleeping sickness control programmes (NSSCPs) succeeded in controlling the disease and reducing the number of cases to historically low levels. In 2012, WHO targeted the elimination of the disease as a public health problem by 2020. This goal has been reached and a new ambitious target was stated in the WHO road map for NTDs 2021-2030 and endorsed by the 73rd World Health Assembly: the elimination of gambiense HAT transmission (i.e. reducing the number of reported cases to zero). The interruption of transmission was not considered as an achievable goal for rhodesiense HAT, as it would require vast veterinary interventions rather than actions at the public health level.
METHODOLOGY/PRINCIPAL FINDINGS
Data reported to WHO by NSSCPs were harmonized, verified, georeferenced and included in the atlas of HAT. A total of 802 cases were reported in 2021 and 837 in 2022. This is below the target for elimination as a public health problem at the global level (< 2000 HAT cases/year); 94% of the cases were caused by infection with T. b. gambiense. The areas reporting ≥ 1 HAT case/10 000 inhabitants/year in 2018-2022 cover a surface of 73 134 km2, with only 3013 km2 at very high or high risk. This represents a reduction of 90% from the baseline figure for 2000-2004, the target set for the elimination of HAT as a public health problem. For the surveillance of the disease, 4.5 million people were screened for gambiense HAT with serological tests in 2021-2022, 3.6 million through active screening and 0.9 million by passive screening. In 2021 and 2022 the elimination of HAT as a public health problem was validated in Benin, Uganda, Equatorial Guinea and Ghana for gambiense HAT and in Rwanda for rhodesiense HAT. To reach the next goal of elimination of transmission of gambiense HAT, countries have to report zero cases of human infection with T. b. gambiense for a period of at least 5 consecutive years. The criteria and procedures to verify elimination of transmission have been recently published by WHO.
CONCLUSIONS/SIGNIFICANCE
HAT elimination as a public health problem has been reached at global level, with seven countries already validated as having reached this goal. This achievement was made possible by the work of NSSCPs, supported by different public and private partners, and coordinated by WHO. The new challenging goal now is to reach zero cases by 2030. To reach this goal is crucial to maintain the engagement and support of donors and stakeholders and to keep the involvement and coordination of all partners. Along with the focus on elimination of transmission of gambiense HAT, it is important not to neglect rhodesiense HAT, which is targeted for elimination as a public health problem in the WHO road map for NTDs 2021-2030.
Topics: Trypanosomiasis, African; Humans; Disease Eradication; World Health Organization; Trypanosoma brucei gambiense; Africa South of the Sahara; Neglected Diseases; Animals; Epidemiological Monitoring
PubMed: 38626188
DOI: 10.1371/journal.pntd.0012111 -
PLoS Neglected Tropical Diseases Apr 2024The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe...
BACKGROUND
The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB.
METHODOLOGY
Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB.
RESULTS
Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite.
CONCLUSION
Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.
Topics: Animals; Mice; Trypanosomiasis, African; Oxidative Stress; Plant Extracts; Ginkgo biloba; Trypanosoma brucei rhodesiense; Melarsoprol; Male; Blood-Brain Barrier; Anti-Inflammatory Agents; Disease Models, Animal; Brain; Antioxidants; Inflammation
PubMed: 38620045
DOI: 10.1371/journal.pntd.0012103 -
Molecules (Basel, Switzerland) Apr 2024Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for...
Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for free. Aiming to validate herbal remedies in use, we selected nine medicinal plants and assessed their antitrypanosomal activity. A total of 122 extracts were prepared using different plant parts and solvents. A total of 15 extracts from seven different plants exhibited in vitro activity (>70% at 20 µg/mL) against bloodstream forms. The dichloromethane extract of (leaves and leaflets) and the ethanolic extract of (leaves) had IC values ≤ 10 µg/mL. These two aquatic plants are of particular interest. They are being co-applied in the form of a decoction of leaves because they are considered by local healers as male and female of the same species, the ethnotaxon "longa dia simbi". Bioassay-guided fractionation led to the identification of eight active molecules: gallic acid (IC 0.5 µg/mL), methyl gallate (IC 1.1 µg/mL), 2,3,4,6-tetragalloyl-glucopyranoside, ethyl gallate (IC 0.5 µg/mL), 1,2,3,4,6-pentagalloyl-β-glucopyranoside (IC 20 µg/mL), gossypetin-7--β-glucopyranoside (IC 5.5 µg/mL), and hypolaetin-7--glucoside (IC 5.7 µg/mL) in , and 5-[(8Z,11Z,14Z)-heptadeca-8,11,14-trienyl] resorcinol (IC 5.3 µg/mL) not described to date in . Five of these active constituents were detected in the traditional preparation. This work provides the first evidence for the ethnomedicinal use of these plants in the management of sleeping sickness in Angola.
Topics: Humans; Animals; Nymphaea; Trypanosomiasis, African; Angola; Seeds; Antiprotozoal Agents; Plant Extracts
PubMed: 38611890
DOI: 10.3390/molecules29071611 -
Medical and Veterinary Entomology Jun 2024Vector control remains one of the best strategies to prevent the transmission of trypanosome infections in humans and livestock and, thus, a good way to achieve the...
The internal transcribed spacer 1 sequence polymorphism brings updates to tsetse species distribution in the northern Cameroon: Importance in planning efficient vector control.
Vector control remains one of the best strategies to prevent the transmission of trypanosome infections in humans and livestock and, thus, a good way to achieve the elimination of human African trypanosomiasis and animal African trypanosomiasis. A key prerequisite for the success of any vector control strategy is the accurate identification and correct mapping of tsetse species. In this work, we updated the tsetse fly species identification and distribution in many geographical areas in Cameroon. Tsetse flies were captured from six localities in Cameroon, and their species were morphologically identified. Thereafter, DNA was extracted from legs of each tsetse fly and the length polymorphism of internal transcribed spacer-1 (ITS1) region of each fly was investigated using PCR. ITS1 DNA fragments of each tsetse species were sequenced. The sequences obtained were analysed and compared to those available in GenBank. This enabled to confirm/infirm results of the morphologic identification and then, to establish the phylogenetic relationships between tsetse species. Morphologic features allowed to clearly distinguish all the tsetse species captured in the South Region of Cameroon, that is, Glossina palpalis palpalis, G. pallicera, G. caliginea and G. nigrofusca. In the northern area, G. morsitans submorsitans could also be distinguished from G. palpalis palpalis, G. tachinoides and G. fuscipes, but these three later could not be distinguished with routine morphological characters. The ITS1 length polymorphism was high among most of the studied species and allowed to identify the following similar species with a single PCR, that is, G. palpalis palpalis with 241 or 242 bp and G. tachinoides with 221 or 222 bp, G. fuscipes with 236 or 237 bp. We also updated the old distribution of tsetse species in the areas assessed, highlighting the presence of G. palpalis palpalis instead of G. fuscipes in Mbakaou, or in sympatry with G. morsitans submorsitans in Dodeo (northern Cameroon). This study confirms the presence of G. palpalis palpalis in the Adamawa Region of Cameroon. It highlights the limits of using morphological criteria to differentiate some tsetse species. Molecular tools based on the polymorphism of ITS1 of tsetse flies can differentiate tsetse species through a simple PCR before downstream analyses or vector control planning.
Topics: Animals; Cameroon; Tsetse Flies; Insect Vectors; Polymorphism, Genetic; Animal Distribution; Phylogeny; DNA, Intergenic; Female; Insect Control; Male; DNA, Ribosomal Spacer; Sequence Analysis, DNA
PubMed: 38563591
DOI: 10.1111/mve.12717 -
PLoS Computational Biology Apr 2024The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two...
The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.
Topics: Animals; Humans; Trypanosomiasis, African; Democratic Republic of the Congo; Models, Theoretical; Forecasting; Markov Chains; Trypanosoma brucei gambiense
PubMed: 38557869
DOI: 10.1371/journal.pcbi.1011993