Article

Human African Trypanosomiasis

October 2009
The Lancet 375(9709):148-59

DOI:10.1016/S0140-6736(09)60829-1

Source
PubMed

Authors:

Reto Brun

Swiss Tropical and Public Health Institute

Johannes Blum

Swiss Tropical and Public Health Institute

Christian Burri

Swiss Tropical and Public Health Institute

Human African trypanosomiasis (sleeping sickness) occurs in sub-Saharan Africa. It is caused by the protozoan parasite Trypanosoma brucei, transmitted by tsetse flies. Almost all cases are due to Trypanosoma brucei gambiense, which is indigenous to west and central Africa. Prevalence is strongly dependent on control measures, which are often neglected during periods of political instability, thus leading to resurgence. With fewer than 12 000 cases of this disabling and fatal disease reported per year, trypanosomiasis belongs to the most neglected tropical diseases. The clinical presentation is complex, and diagnosis and treatment difficult. The available drugs are old, complicated to administer, and can cause severe adverse reactions. New diagnostic methods and safe and effective drugs are urgently needed. Vector control, to reduce the number of flies in existing foci, needs to be organised on a pan-African basis. WHO has stated that if national control programmes, international organisations, research institutes, and philanthropic partners engage in concerted action, elimination of this disease might even be possible.

The comprehensive epidemiological status of human African trypanosomiasis in Nigeria: meta-analysis and systematic review of the full story (1962–2022)

Article

Full-text available

Aug 2024
Parasitol Res

Human African trypanosomiasis (HAT) in Nigeria is caused primarily by Trypanosoma brucei gambiense (gHAT), which has historically been a major human and animal health problem. This study aims to examine the status of gHAT in Nigeria over the past 60 years. The World Health Organization (WHO) set two targets to eliminate HAT as a public health concern by 2020 and terminate its global transmission by 2030. The former target has been achieved, but accurate monitoring and surveillance are important for maintaining this success and delivering the second target. Although recent cases in Nigeria are rare, accurately estimating the national seroprevalence and actual prevalence of gHATs remains challenging. To address this, a meta-analysis reviewed studies on gHATs in Nigeria from databases such as Embase, Global Health, Ovid Medline, Web of Science, and Google Scholar. Ten studies were included, ranging between 1962 and 2016, covering 52 clusters and 5,671,877 individuals, even though databases were scrutinized up to 2022. The seroprevalence ranged from 1.75 to 17.07%, with an overall estimate of 5.01% (95% CI 1.72–9.93). The actual gHAT prevalence detected by parasitological or PCR methods was 0.001 (95% CI 0.000–0.002), indicating a prevalence of 0.1%. Notably, the seroprevalence was greater in southern Nigeria than in northern Nigeria. These findings suggest that the disease might be spreading unnoticed due to the increased movement of people from endemic areas. This study highlights the paucity of studies in Nigeria over the last 60 years and emphasizes the need for further research, systematic surveillance, and proper reporting methods throughout the country.

Possible Chemotherapeutic Potential of Inhibiting N-Alpha Terminal Acetylation Activities to Combat Trypanosome Infections

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Nov 2023

Stephen Ochaya

New anti-trypanosome drugs focusing on N-alpha terminal acetylation (Nt-acetylation) interference are necessary scientific inputs because currently, many of the drugs in use are unacceptably toxic; moreover, resistance is emerging. Nt-acetylation transfers an acetyl molecule to the N-alpha terminal of a protein by enzymes called N-alpha terminal acetyltransferases (Nats). Nats are grouped according to their amino acid sequence at the N-terminus where they acetylate. It is conserved in all kingdoms of life, and in humans, approximately 80% of proteins are thought to be Nt-acetylated. NatA-NatF and NatH identified in humans, and NatG has been observed in plants. Nats play critical roles in several cellular processes and integrity and have been suggested as possible drug targets to control different cancer diseases. NatA and NatC have been partially characterized in trypanosomes and shown to be essential for parasite viability. Biologically, the way parasites program their lives is embedded in their unique organelles, metabolic pathways, gene regulation, epigenetic gene activities, and many virulence factors including surface molecules. These characteristics and the different protein-coding genes involved could be Nt-acetylated, and the inhibition of Nats can deny the ability of trypanosomes to survive in any environment because many proteins can be simultaneously affected.

Vertex-Based Resolvability Parameters for Identification of Certain Chemical Structures

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Chemical graph theory explores chemical phenomena and entities through the conceptual framework of graph theory. In chemical graph theory, molecular structures are represented by chemical graphs, where edges and vertices correspond to bonds and atoms, respectively. Chemical graphs serve as fundamental data types in cheminformatics for illustrating chemical structures. The computable properties of graphs form the basis for quantitative structure–property and structure–activity predictions, which are central to cheminformatics. These graphs capture the physical characteristics of molecules and can be further reduced to graph-theoretical indices or descriptors. One extensively studied distance-based graph descriptor is the resolving set Z, which enables the distinction of every pair of distinct vertices in a connected simple graph. Resolving sets were specifically employed in pharmaceutical research to find patterns shared by several different drugs. Since very early times, medicinal drugs have played a significant part in human civilization. In this article, we investigate minimum resolving sets for certain significant drug molecular structures, namely, suramin (S86) and acemannan (A116)

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

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Aug 2023
INT J MOL SCI

Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite Trypanosoma brucei, and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed.

In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs

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Jul 2023
MOL DIVERS

Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin (1), and its analogs (2–24) were tested against bloodstream forms of T. brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, T. equiperdum, and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX (1)] demonstrated selective trypanocidal activity against T. congolense (IC50 7.79 µM; SI 39.6), whereas the CPX derivatives (2–10) showed weak selective activity (25 < IC50 < 65 µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids (11–24) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX (1); CPX amide derivatives 18: IC50 8.95 µM; SI 16.84; 22: IC50 5.42 µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC50 4.51 µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho-, meta-, and/or para-substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity. Graphical abstract Structure–activity relationships of ciprofloxacin-1,2,3-triazole hybrids were governed by the chemical functionality at C-3 and electronic effect.

Implications of Nano-Biosensors in the Early Detection of Neuroparasitic Diseases

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Mar 2024

Parasitic diseases affecting millions of people globally cause fatalities and incapacitating conditions. It is, therefore, essential to detect parasitic diseases by looking for the parasite/s or their specific proteases that they produce at different phases of their life cycles. Numerous symptoms and indicators can result from a parasitic infection of the neurological system, but it is still challenging to diagnose an infection because the symptoms are frequently vague or minor. It is more likely that a parasite infection of the nervous system will be identified and treated well if one is familiar with fundamental epidemiological traits and distinctive radiography findings. For accurate diagnosis of these neurological disorders, proper identification and adoption of acceptable public health measures for the management of epidemic outbreaks are required. For numerous diseases, conventional in vitro techniques are time-consuming and need centralized facilities. So, the development of biosensor technology could lead to point-of-care diagnostics that are as accurate, fast, and affordable as or better than current standards. Modern biosensors include varied sensing techniques, such as optical, electrical, and mechanical transducers, as well as micro- and nanofabrication technologies. Only a handful of well-known biosensor examples have successfully transitioned from laboratory research to clinical applications despite the need for the medical community. Biosensor-based diagnosis of protozoan diseases like malaria, leishmaniasis, American trypanosomiasis (Chagas disease), and toxoplasmosis has been accomplished but is still in the infancy stage. In addition to the advancements in biosensors for the diagnosis of parasitic infections, we highlight the considerable challenges that must be overcome in order to bring integrated diagnostic biosensors into use in real-world scenarios.

Trypanosomiasis – Update on Laboratory Diagnosis and Treatment

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Trypanosomes are hemoflagellates that reside in peripheral blood and tissues of the host caused by infection with protozoan parasites belonging to the genus Trypanosoma. Types: Human African Trypanosomiasis – HAT (sleeping sickness) &American Trypanosomiasis (Chagas’ disease). Metacyclic trypomastigotes is the infective form. C/F includes Fever, headaches, irritability, extreme fatigue, swollen lymph nodes, aching muscles and joints. Chronic Chagas’: cardiomyopathy with congestive heart failure. Diagnosis: examination of blood smears during the acute disease usually shows trypomastigotes. Serologic testing is used for screening purposes only. PCR of kDNA may also be used. Isothermal amplification technology (i.e., RPA or LAMP), possibly enhanced by combining it with a highly specific CRISPR-Cas step, will fulfil all the requirements of a modern target product profile for HAT diagnosis. Drugs used are Pentamidine, Suramin (first stage) & Melarsoprol, Eflornithine, Nifurtimox (second stage). Fexinidazole is used in both stages. Newer drugs include Pafuramidine & Acoziborole

Prevalence of Spiroplasma and interaction with wild Glossina tachinoides microbiota

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Dec 2023
Parasite

Tsetse flies (Diptera: Glossinidae) are vectors of the tropical neglected diseases sleeping sickness in humans and nagana in animals. The elimination of these diseases is linked to control of the vector. The sterile insect technique (SIT) is an environment-friendly method that has been shown to be effective when applied in an area-wide integrated pest management approach. However, as irradiated males conserve their vectorial competence, there is the potential risk of trypanosome transmission with their release in the field. Analyzing the interaction between the tsetse fly and its microbiota, and between different microbiota and the trypanosome, might provide important information to enhance the fly’s resistance to trypanosome infection. This study on the prevalence of Spiroplasma in wild populations of seven tsetse species from East, West, Central and Southern Africa showed that Spiroplasma is present only in Glossina fuscipes fuscipes and Glossina tachinoides. In G. tachinoides, a significant deviation from independence in co-infection with Spiroplasma and Trypanosoma spp. was observed. Moreover, Spiroplasma infections seem to significantly reduce the density of the trypanosomes, suggesting that Spiroplasma might enhance tsetse fly’s refractoriness to the trypanosome infections. This finding might be useful to reduce risks associated with the release of sterile males during SIT implementation in trypanosome endemic areas.

Pyrazolyl amide-chalcones conjugates: Synthesis and antikinetoplastid activity

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N Schmied Arch Pharmacol

A series of novel pyrazolyl amide-chalcones conjugates was synthesized in five steps and evaluated against a range of medically important kinetoplastid parasites including Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. In addition, the series was also tested for in vitro cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all synthetised compounds, 9b was found to be the most active against T. b. brucei with an IC50 value of 0.51 ± 0.06 μM. Against T. b. rhodesiense, 9n was found to be the most potent with an IC50 value of 0.46 ± 0.07 μM. While against L. infantum, 9a was found to be most active with an IC50 value of 7.16 ± 1.88 μM. Based on the results and SAR, further modifications will be carried out to increase potency. Graphical Abstract

Pharmacophore Identification and Structure-Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of Trypanosoma brucei

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Aug 2024
J MED CHEM

Human African trypanosomiasis is among the World Health Organization’s designated neglected tropical diseases. Repurposing strategies are often employed in academic drug discovery programs due to financial limitations, and in this instance, we used human kinase inhibitor chemotypes to identify substituted 4-aminoazaindoles, exemplified by 1. Structure–activity and structure–property relationship analysis, informed by cheminformatics, identified 4s as a potent inhibitor of Trypanosoma brucei growth. While 4s appeared to be fast acting and cidal in the in vitro assays, it failed to cure a murine model of infection. Preliminary efforts to identify the potential mechanism of action of the series pointed to arginine kinase, though, as we demonstrate, this does not appear to be the sole target of our compounds. This comprehensive approach to drug discovery, encompassing cheminformatics, structure–potency and structure–property analysis, and pharmacophore identification, highlights our multipronged efforts to identify novel lead compounds for this deadly disease.

The Influence of Environmental Conditions and Coinfection by Blood-Feeding Parasites on Red Blood Cell Physiology of an Ectothermic Host

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Structural insights into drug transport by an aquaglyceroporin

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Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.

Discovery of Strong 3-Nitro-2-Phenyl-2H-Chromene Analogues as Antitrypanosomal Agents and Inhibitors of Trypanosoma cruzi Glucokinase

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Apr 2024
INT J MOL SCI

Chagas disease is one of the world’s neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. 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. T. cruzi glucokinase (TcGlcK) 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 TcGlcK inhibitors that also exhibited anti-T. cruzi efficacy called the 3-nitro-2-phenyl-2H-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 TcGlcK 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 T. cruzi 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 GLK2-003 and GLK2-004 were determined to inhibit TcGlcK quite well with IC50 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-2H-chromene analogues, two of which were GLK2-003 and GLK2-004 (compounds 1 and 9, respectively). Twelve of these compounds had a one-point change from the chemical structure of GLK2-003. 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) T. cruzi (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) T. brucei brucei (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the TcGlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC50 determinations, and an assessment of structure–activity relationships. Our results reveal that the 3-nitro-2-phenyl-2H-chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.

Role of Organometallic Compounds in Neglected Tropical Diseases

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Putative bloodmeal sources in Glossina austeni tsetse fly of Arabuko Sokoke National Reserve in Kenya

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PLOS ONE

Tsetse flies, the sole biological vectors of trypanosomiasis, are predominantly controlled using visual traps and targets baited with attractant lures. Formulation of the lures is informed by compositions of odors from vertebrate hosts preferred by specific tsetse species. However, there are no effective lures for Glossina austeni, a major vector of trypanosomiasis along eastern-coastal region of Africa. Formulation of the lure can be informed by knowledge of G. austeni, preferred vertebrate hosts. We thus sought to understand these hosts by assessment of putative bloodmeal sources of this tsetse fly in Arabuko Sokoke National Reserve where this species is naturally present. We sampled tsetse flies using NGU traps, isolated non-teneral G. austeni flies based on their feeding status, and identified vertebrate source of bloodmeals in their midgut contents using vertebrate 16S rRNA-PCR High-Resolution Melting analysis. We analyzed the relative vertebrate species frequencies in the bloodmeals using Fisher’s exact tests. Overall, we trapped 122 flies, most of which (66.39%) were non-teneral, among which we successfully identified the vertebrate bloodmeals in 30 samples. Specifically, we detected putative suni antelope (Neotragus moschatus), harnessed bushbuck (Tragelaphus scriptus), buffalo (Syncerus caffer) and cattle (Bos taurus) derived bloodmeals. Putative suni antelope bloodmeals were significantly more frequent (63.22%), than those of the harnessed bushbuck (23.33%), buffalo (10.00%) or cattle (3.33%) (p < 0.05 Fisher’s exact tests) among the samples analyzed. Suni antelope thus appears to predominate vertebrate bloodmeal source for G. austeni in the reserve, coincident with findings reported elsewhere, and is therefore a viable candidate for bioprospecting for G. austeni responsive attractants.

Assessment of Serum Proinflammatory Cytokines and Some Associated Haematobiochemical Indices in An experimental Canine Trypanosomiasis

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Purpose Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer. Methods A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. Results After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28–105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity. Conclusion The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.

Targeting RNA Structure to Inhibit Editing in Trypanosomes

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INT J MOL SCI

Mitochondrial RNA editing in trypanosomes represents an attractive target for developing safer and more efficient drugs for treating infections with trypanosomes because this RNA editing pathway is not found in humans. Other workers have targeted several enzymes in this editing system, but not the RNA. Here, we target a universal domain of the RNA editing substrate, which is the U-helix formed between the oligo-U tail of the guide RNA and the target mRNA. We selected a part of the U-helix that is rich in G-U wobble base pairs as the target site for the virtual screening of 262,000 compounds. After chemoinformatic filtering of the top 5000 leads, we subjected 50 representative complexes to 50 nanoseconds of molecular dynamics simulations. We identified 15 compounds that retained stable interactions in the deep groove of the U-helix. The microscale thermophoresis binding experiments on these five compounds show low-micromolar to nanomolar binding affinities. The UV melting studies show an increase in the melting temperatures of the U-helix upon binding by each compound. These five compounds can serve as leads for drug development and as research tools to probe the role of the RNA structure in trypanosomal RNA editing.

Ticks as vectors of Trypanosomatidae with medical or veterinary interest: Insights and implications from a comprehensive systematic review and meta-analysis

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For over a century, researchers have grappled with a compelling question: can ticks act as vectors for Trypanosomatidae parasites, such as Trypanosoma and Leishmania species, which pose significant threats to human and animal health? A recent systematic review and meta-analysis provides new evidence that could reshape our understanding of tick-borne diseases. This study, spanning over 110 years of research (1912–2023), analyzed 94 field studies and synthesized data from 86 quantitative papers. The findings are striking: Trypanosomatidae parasites were detected in 15.48% of ticks [7.99-24.61%], with infections varying by geography, detection methods, and tick genera. Most infected species were from Amblyomma, Hyalomma, Ixodes, and Rhipicephalus. Notably, experimental studies also revealed that ticks in both Argasidae and Ixodidae families may have vector competence via non-traditional transmission routes. Despite compelling evidence of natural infections and laboratory demonstrations of parasite-tick interactions, the study acknowledges that the exact role of ticks as biological or mechanical vectors remains inconclusive. However, this uncertainty is precisely what makes the findings so impactful. By identifying significant gaps in our understanding, the research emphasizes the urgent need for targeted investigations to confirm the potential role of ticks in the epidemiology of Trypanosomatidae-related diseases. The implications of this study are profound. If ticks are indeed vectors, they could play a previously overlooked role in the transmission of diseases affecting millions globally. This realization would demand a reassessment of current vector control strategies, particularly in endemic regions where ticks and Trypanosomatidae coexist. This comprehensive review offers a fresh perspective and serves as a call to action for researchers and public health practitioners. The potential for ticks to act as vectors may redefine how we combat these parasitic diseases in the future.

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Almonther Hershan

Dengue is a viral infection caused by one of four serotypes of dengue virus (DENV), which is responsible for causing potentially life-threatening disease and substantial public health as well as economic burden worldwide. The non-structural and structural proteins of DENV are essential to its viral activity and pathogenesis. Unfortunately, despite numerous efforts, there is still no cure for dengue. Most of the available therapeutic options only provide symptomatic treatment. Since there is a lack of cure and dengue-related substantial economic and public health burden, a safe and effective dengue vaccine is urgently required. Currently, there is only one approved dengue vaccine available that provides suboptimal protection; however, a range of other dengue vaccines are under development to lower the infection burden and decrease dengue morbidities. In addition, numerous dengue therapeutics are also being developed, which have great potential in dengue treatment. These therapeutics mostly act by decreasing viral replication, vascular pathologies, and/or inflammation. This review comprehensively summarizes the latest update on dengue vaccines and therapeutics. Moreover, various other important aspects of DENV, including molecular biology, pathogenesis, and control strategies, have also been discussed.

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Human African Trypanosomiasis (HAT)

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Human African Trypanosomiasis (HAT) found only in sub-Saharan Africa is caused by the parasite Trypanosoma brucei, which is transmitted by tsetse flies. Only two sub-species of T. brucei are pathogenic for humans: T. b. gambiense and T. b. rhodesiense. HAT is endemic in 36 sub-Saharan countries, and 98% of all reported HAT cases are due to T. b. gambiense. Fifty-five million persons in Africa are at risk of HAT. The number of HAT cases reported globally decreased fivefold in the last decade, which encouraged WHO to set a target to eliminate HAT as a public health problem by the year 2020, aiming for zero transmission by the year 2030. Tsetse flies do not lay eggs, but the female fly deposits a single mature larva in humid soil. The larva pupates and emerges as an adult fly 20 to 80 days later. A female fly produces only 3–5 larvae during her lifetime that typically lasts for 3 months making the intrinsic growth rate of tsetse populations rather low. An infected tsetse fly injects the infective form of the parasites into the mammalian host when it feeds. These parasites undergo, and can switch, their antigenic variation of their variant surface glycoprotein (VSG) coat, allowing them to escape the host immune response. This phenomenon of antigenic variation makes the development of an effective vaccine unlikely. The disease affects mainly the lymphoid system, heart, lungs, and brain, manifesting as intermittent fever, general malaise, severe headache, joint pains and muscle aches, pruritus, urticaria, or facial oedema. Lymphadenopathy is common with the classical Winterbottom’s sign. Patients with the meningo-encephalitic stage suffer continuous headaches with poor response to painkillers and show more specific neurological signs of the rather typical sleep disturbances. Diagnosis of HAT is a three-step procedure: (1) screening test to identify HAT suspects, (2) confirmatory parasitological tests, and (3) staging. Treatment is based on the stage of illness, with current options being pentamidine, suramin, melarsoprol, eflornithine, fexinidazole, and the nifurtimox-eflornithine combination therapy (NECT). Two strategies are used for the reduction or interruption of HAT transmission: elimination of the parasite reservoir and vector control. This last decade has seen several breakthroughs in clinical R&D for HAT, bringing new diagnostics and drugs to patient care, but the effective and efficient implementation of these new tools in HAT control and proper treatment of patients will require further research.

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Human African Trypanosomiasis (Sleeping Sickness)

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Synthesis and biological evaluation of orally active anti-Trypanosoma agents

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Comparison of Three Widely Employed Extraction Methods for Metabolomic Analysis of Trypanosoma brucei

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Trypanosoma brucei (Tb) is the causative agent of human African trypanosomiasis (HAT), also known as sleeping sickness, which can be fatal if left untreated. An understanding of the parasite's cellular metabolism is vital for the discovery of new antitrypanosomal drugs and for disease eradication. Metabolomics can be used to analyze numerous metabolic pathways described as essential to Tb. brucei but has some limitations linked to the metabolites’ physicochemical properties and the extraction process. To develop an optimized method for extracting and analyzing Tb. brucei metabolites, we tested the three most commonly used extraction methods, analyzed the extracts by hydrophilic interaction liquid chromatography high‐resolution mass spectrometry (HILIC LC‐HRMS), and further evaluated the results using quantitative criteria including the number, intensity, reproducibility, and variability of features, as well as qualitative criteria such as the specific coverage of relevant metabolites. Here, we present the resulting protocols for untargeted metabolomic analysis of Tb. brucei using (HILIC LC‐HRMS). © 2024 Wiley Periodicals LLC. Basic Protocol 1 : Culture of Trypanosoma brucei brucei parasites Basic Protocol 2 : Preparation of samples for metabolomic analysis of Trypanosoma brucei brucei Basic Protocol 3 : LC‐HRMS‐based metabolomic data analysis of Trypanosoma brucei brucei

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Jan 2024

Kiswendsida Mikhailou Dera

The progress of sub-Saharan African nations is contingent upon various factors, including health considerations. Among health concerns, neglected tropical diseases present widespread challenges in these countries, resulting in significant consequences. African trypanosomosis, encompassing Human African Trypanosomosis (HAT) or sleeping sickness in humans and Animal African Trypanosomosis (AAT) or nagana in animals, stand out as major neglected tropical diseases prevalent in sub-Saharan Africa. These diseases are transmitted by tsetse flies, serving as cyclical vectors. The absence of a preventive vaccine and effective treatment underscores the challenges in controlling trypanosomosis. Vector control emerges as a potent strategy, given the limitations associated with vaccination and treatment. In response to the environmental repercussions of chemical approaches against tsetse, an ecologically sustainable alternative has been devised—the Sterile Insect Technique (SIT). SIT involves the release of sterile males to compete with their wild counterparts for mating with wild females, yielding no progeny from these encounters. This technique has proven highly efficacious, particularly if applied within the framework of Area-Wide Integrated Pest Management (AW-IPM) programs. However, several constraints affect the efficacy of the SIT. These include challenges in mass-rearing to produce competitive sterile males and concerns about the vectorial competence of the released sterile males. To mitigate the potential of transmitted trypanosomes, various treatments are administered prior to release. A primary intervention involves supplementing the blood meal of sterile males with the trypanocidal drug isometamidium chloride. However, it is important to note that this treatment does not afford complete and comprehensive protection against all trypanosome species. Therefore, it is imperative to assess novel tools aimed at enhancing refractoriness to trypanosome infection. Various studies have yielded noteworthy insights into the pivotal role of the microbiota in tsetse flies. Notably, these flies host four endosymbionts Wigglesworthia glossinidia, Wolbachia pipientis, Sodalis glossinidius and Spiroplasma that significantly influence their biology. Understanding the intricate interplay among this microbiota, trypanosomes, and the tsetse fly holds the potential for substantial advancements in the SIT. Notably, the latter two endosymbionts have been suggested to be implicated in inducing refractoriness to trypanosome infections in the fly. The aim of this thesis was to contribute to the improvement of mass rearing for SIT by comprehensively evaluating of the impact of Spiroplasma. The research encompasses critical investigations, including (i) assessing the prevalence of Trypanosoma and Sodalis in wild tsetse fly populations and their implications for SIT, (ii) examining the prevalence of Spiroplasma and its interaction with the microbiota of wild Glossina tachinoides, (iii) evaluating the impact of endosymbiotic Spiroplasma infection on the metabolic and reproductive homeostasis of Glossina fuscipes fuscipes, and (iv) appraising the influence of Spiroplasma infection in a colonized Glossina fuscipes fuscipes colony on mass rearing and SIT. The research employs diverse molecular biology techniques throughout the investigation on wild and colonized tsetse flies spanning various taxa and geographic locations. The findings confirm a close relationship between Sodalis and Trypanosoma; however, this interaction seems to depend on the specific trypanosome or tsetse species and location. Notably, a significant correlation was identified between Sodalis and trypanosome infection in G. medicorum, G. palpalis gambiensis, and G. pallidipes. Regarding the endosymbiont Spiroplasma, its presence was exclusively noted in flies of the Palpalis group, particularly G. f. fuscipes and G. tachinoides. Moreover, G. tachinoides flies harbouring Spiroplasma exhibited lower Trypanosoma infection rates, suggesting that Spiroplasma presence might confer refractoriness to trypanosome infection in the fly. However, in colonized G. f. fuscipes, the presence of Spiroplasma seems to disadvantage the fly. Specifically, Spiroplasma induces sex bias gene expression and prolongs the gonotrophic cycle in infected females. Additionally, infected males exhibit less motile sperm compared to their uninfected counterparts. Finally, under mass-rearing conditions, G. f. fuscipes females harbouring Spiroplasma display reduced fecundity compared to uninfected females. The presence of Spiroplasma also reduces fly survival and male competitiveness in field cage conditions. The outcomes of this research thesis yield significant insights that can inform strategies for enhancing mass rearing in the context of the Sterile Insect Technique (SIT).

What a twist: structural biology of the SARS-CoV-2 helicase nsp13

Article

Feb 2024

Novel quinoline derivatives with broad-spectrum antiprotozoal activities

Article

Full-text available

Feb 2024
ARCH PHARM

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for sleeping sickness (Trypanosoma brucei rhode-siense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC 50) values of 0.68, 0.8, and 0.19 µM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages (∼100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC 50 values of 1.4 and 0.4 µM, respectively. K E Y W O R D S anti-infectives, arylnitro, chalcones, protozoal, quinoline

Antitrypanosomal Chloronitrobenzamides

Article

Feb 2024
J MED CHEM

Opportunities and Difficulties in the Repurposing of HDAC Inhibitors as Antiparasitic Agents

Article

Full-text available

Jan 2024

Ongoing therapy for human parasite infections has a few known drugs but with serious side effects and the problem of drug resistance, impelling us to discover novel drug candidates with newer mechanisms of action. Universally, this has boosted the research in the design and development of novel medicinal agents as antiparasitic drugs with a novel mode of action. Histone deacetylase inhibitors (HDACis) are used in a vast variety of diseases due to their anti-inflammatory properties. Drug repurposing strategies have already approved HDACis as cancer therapeutics and are now under investigation for many parasitic infections. Along with the expression of the gene, histone deacetylase (HDAC) enzymes also act as a slice of great multi-subunit complexes, targeting many non-histones, changing systemic and cellular levels signaling, and producing different cell-based specified effects. Zinc (Zn2+)- and nicotinamide adenine dinucleotide (NAD+)-dependent HDACs of parasites play pivotal roles in the alteration of gene expression of parasites. Some of them are already known to be responsible for the survival of several parasites under odd circumstances; thus, targeting them for therapeutic interventions will be novel for potential antiparasitic targets. This point of view outlines the knowledge of both class-I and class-II HDACis and sirtuin inhibitors that emerged to be the key players in the treatment of human parasitic disorders like Leishmaniasis, Schistosomiasis, Malaria, Trypanosomiasis, and Toxoplasmosis. This review also focuses on repurposing opportunities and challenges in HDAC inhibitors that are preceded by their clinical development as potent new antiparasitic drugs.

Parasitic infections of the central nervous system

Chapter

Jan 2024

Biosynthesis of ergosterol as a relevant molecular target of metal-based antiparasitic and antifungal compounds

Article

Jan 2024
COORDIN CHEM REV

Trypanosomatid parasites and fungi cause highly prevalent diseases. Ergosterol plays a crucial role in the structure and normal function of the membrane of these microorganisms. It is absent in mammals. Many enzymes of the ergosterol biosynthesis route have been recognized as molecular targets for drugs. Currently, a variety of organic drugs that interfere with sterol biosynthesis are employed to treat fungal infections, and some of them have been proposed as potential treatments for trypanosomiasis. Coordinating these organic drugs to metal ions may positively impact the biological performance by altering relevant physicochemical properties. Additionally, their organometallic derivatization could improve the effectiveness. This comprehensive review aims to highlight the considerable promise of metal-based compounds as inhibitors of essential pathways or key enzymes of these microorganisms, with focus on the ergosterol biosynthesis pathway. Additionally, bioactive metal compounds that have demonstrated experimental efficacy in acting on enzymes within this pathway although not designed for this purpose were included. The current state of the art demonstrates the impressive but still underexplored potential of these metal-based compounds for treating fungal and trypanosomatid infections.

Climate Change Impacts, Adaptation and Mitigation Strategies in Tanzania

Chapter

Jan 2024

The United Republic of Tanzania is among the countries that has experienced impacts of climate change including epidemics of climate-sensitive infectious diseases, food and nutrition insecurity. Others include damage to infrastructure caused by flooding and land slides resulting to human injuries, deaths and displacement, and high cost to restore the damaged infrastructure. The climate-sensitive diseases that have occurred in Tanzania include dengue, chikungunya, malaria, Rift Valley fever, leptospirosis, cholera and Human African Trypanosomiasis. The country has recently developed a National Climate Change Strategic Plan to provides a set of interventions on adaptation and mitigation, which are expected to strengthen country’s resilience to the impacts of climate change and contribute to the global efforts of reducing greenhouse gas emissions. In addition, the country has developed the Health-National Adaptation Plan to climate change to guide the towards a health system that is more resilient to climate change. However, the efficiency of the operationalization of these strategies are not sufficiently known.

Exploring microalgal and cyanobacterial metabolites with antiprotozoal activity against Leishmania and Trypanosoma parasites

Article

Dec 2023
ACTA TROP

Impact of a small-scale tsetse fly control operation with deltamethrin impregnated “Tiny Targets” on tsetse density and trypanosomes’ circulation in the Campo sleeping sickness focus of South Cameroon

Article

Full-text available

Nov 2023
PLOS NEGLECT TROP D

Background Significant progress has been made towards African sleeping sickness elimination in the last decade. Indeed, the World Health Organization (WHO) global goal of eliminating the chronic form of the disease as a public health problem was achieved in 2020 (i.e., < 2,000 new cases per year). Vector control has played an important role in achieving this goal. In this study, we evaluated the impact of the insecticide impregnated Tiny Targets on tsetse fly densities and their infection rates with Trypanosoma spp in the Campo sleeping sickness focus of South Cameroon. Methods The study site was divided into two areas: (i) the south-west experimental area, which included vector control, and (ii) the eastern part as the non-intervention area. After compiling the baseline entomological data (tsetse densities and trypanosome infection rates), around 2000 Tiny Targets were deployed in the South-West area and replaced every six months for two years. Post-intervention surveys were conducted every six months to determine tsetse densities and levels of trypanosome infections with PCR-based methods. Results Following the intervention, tsetse mean catches decreased by 61% after six months, and up to 73% after twelve months (pre-intervention: 2.48 flies/trap/day, 95%CI [1.92–3.14]; 12-months post-intervention: 0.66 tsetse/trap/day, 95%CI [0.42–0.94]). This decrease was not sustained after 18 months, and the mean catch doubled compared to that after 12 months. After 24 months, the mean catches still increased by 17% (18 months: 1.45 tsetse/trap/day, 95%CI [1.07–1.90] and 24 months: 1.71 tsetse/trap/day, 95%CI [1.27–2.24]). In the non-intervention area, a variation in tsetse catches was observed during the two years, with a general increase from 2.43 [0.73–5.77] to 3.64 [1.47–7.70] tsetse/trap/day. In addition, trypanosome infection rates dropped by 75% in both areas (P-value < 0.001) from 21.20% to 5.06% and from 13.14% to 3.45% in intervention and control areas respectively. Conclusion Tiny targets have proven useful in reducing tsetse population densities and trypanosome infection rates, providing evidence for the integration of this tool in current strategies towards trypanosomiasis elimination in Campo. The non-sustained decrease of tsetse densities after one year may indicate reinvasions from neighbouring breeding sites or that the intervention area was not large enough. Our results show the need to scale up by accessing difficult breeding sites and extend the tiny targets to the whole transborder focus.

Promising Compounds of Plant Origin and Their Synthetic Analogs Against Trypanosomes

Chapter

Nov 2023

There are about 20 species of the genus Trypanosoma, but among them only a few subspecies—Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, and Trypanosoma cruzi mainly cause disease in humans. The main causative agent of human African trypanosomiasis (HAT) or sleeping sickness is Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. HAT disease is a parasitic disease spread by vectors and has serious health and financial issues in rural sub-Saharan Africa. Infections by Trypanosoma sp. are prevalent in many countries of Mexico, Africa, and Central and South America, which can cause serious public health and epizootic problems. Several control programs pertaining to decreasing the disease risk are carried out in infection-prone areas; for example, vector eradication and treatment of infected people by drug are in operation in these regions. These control strategies are not that successful in solving the problem of trypanosomiasis due to several reasons which stand in the way of effective control. Chemoprophylaxis is an effective way of treatment in these areas, but it is not an effective preventive measure. Several drugs that were discovered for the treatment in the early twentieth century, like pentamidine, tryparsamide, atoxyl, and suramin, were incapable of crossing the blood–brain barrier in substantial amount to avoid the recurrence of trypanosomiasis at an advanced stage, which primarily concerned with parasite gradual invasion in the central nervous system. Till today, no vaccines are available in order to prevent the transmission of trypanosomes. Therefore, treatment of trypanosomiasis is unsatisfactory in the current scenario. Failure of chemical-based allopathic drugs and their serious side effects have increased the awareness among the people about health concerns, which leads to a shift in their preferences for traditional plant-based drugs for curing this disease. For ages, knowledge of traditional plant-based drugs has been explored due to the existence of pharmacologically active compounds. These pharmacologically active natural compounds offer a lot of potential for novel medication development, and their changed derivatives can be more effective against pathology and have lower toxicity. Therefore, there is a pressing need to study natural compounds for the treatment of trypanosomiasis. This book chapter focuses on a number of promising natural anti-trypanosomiasis substances that might be investigated further for medication development.

Strategies and Challenges for Developing Plant-Based Therapeutics Against Protozoans

Chapter

Nov 2023

Several protozoan parasites are known to cause severe human and zoonotic infections as well as life-threatening diseases including trypanosomiasis, leishmaniasis and malaria. These diseases cause high mortality and morbidity in developing countries across the world and yet remain a neglected public health issue. Currently, available chemotherapeutic drugs against these parasitic protozoans are either ineffective or exhibit severe side effects and also result in the development of resistance. To overcome these problems, phytochemicals have shown an ingenious way to provide innumerable molecules exhibiting great potential for the management of protozoan infection and diseases along with safety for humans and the environment. Several studies across the globe have provided evidence for the presence of bioactive components through in vitro, in vivo and clinical screening of phytochemicals. These bioactive compounds present in the crude extracts and essential oils of medicinal plants are quintessential components for strategies to develop plant-based therapeutics against Protozoans. This chapter highlights the potential of plant-based compounds as powerful anti-protozoan drugs and future challenges to fight against parasitic infection.

Protozoans Attacking Humans

Chapter

Nov 2023

Heinz Mehlhorn

This chapter defines the characteristics of protozoan parasites including important species of the flagellates, amoebae, trypanosomes, Leishmania species and Coccidia (including species of the genera Isospora, Cyclospora, Cryptosporidium, Sarcocystis, Toxoplasma, Plasmodium, Babesia, Balantidium, Pneumocystis, Blastocystis, Enterocytozoon, Septata, Encephalitozoon and Nosema). Each species description contains the single topics: name, geographic distribution, biology/morphology, symptoms of disease, diagnosis, pathway of infection, prophylaxis, incubation period, prepatent period, patency, chemotherapy and further reading.

The pathogenicity of blood stream and central nervous system forms of Trypanosoma brucei rhodesiense trypanosomes in laboratory mice: a comparative study

Article

Full-text available

Nov 2023

Background: Human African trypanosomiasis (HAT) develops in two stages namely early stage when trypanosomes are found in the blood and late stage when trypanosomes are found in the central nervous system (CNS). The two environments are different with CNS environment reported as being hostile to the trypanosomes than the blood environment. The clinical symptoms manifested by the disease in the two environments are different. Information on whether blood stream are pathologically different from CNS trypanosomes is lacking. This study undertook to compare the inter-isolate pathological differences caused by bloodstream forms (BSF) and central nervous system (CNS) of five Trypanosoma brucei rhodesiense ( Tbr) isolates in Swiss white mice. Methods: Donor mice infected with each of the five isolates were euthanized at 21 days post infection (DPI) for recovery of BSF trypanosomes in heart blood and CNS trypanosomes in brain supernatants. Groups of Swiss white mice (n = 10) were then infected with BSF or CNS forms of each isolate and monitored for parasitaemia, packed cell volume (PCV), body weight, survivorship, trypanosome length, gross and histopathology characteristics. Results: Amplification of SRA gene prior to trypanosome morphology and pathogenicity studies confirmed all isolates as T. b. rhodesiense. At 21 DPI, CNS trypanosomes were predominantly long slender (LS) while BSF were a mixture of short stumpy and intermediate forms. The density of BSF trypanosomes was on average 2-3 log-scales greater than that of CNS trypanosomes with isolate KETRI 2656 having the highest CNS trypanosome density. Conclusions: The pathogenicity study revealed clear differences in the virulence/pathogenicity of the five (5) isolates but no distinct and consistent differences between CNS and BSF forms of the same isolate. We also identified KETRI 2656 as a suitable isolate for acute menigo- encephalitic studies.

Long-Term Effects of Suramin on Renal Function in Streptozotocin-Induced Diabetes in Rats

Article

Full-text available

Sep 2023
INT J MOL SCI

In short-term diabetes (3 weeks), suramin, a drug used clinically, affects renal function and the expression of vascular endothelial growth factor A (VEGF-A), which may be involved in the pathogenesis of diabetic nephropathy, the main cause of end-stage renal disease. In the present study, we evaluated the long-term (11 weeks) effects of suramin (10 mg/kg, i.p., once-weekly) in diabetic rats. Concentrations of VEGF-A, albumin, soluble adhesive molecules (sICAM-1, sVCAM-1), nucleosomes, and thrombin-antithrombin complex (TAT) were measured by ELISA, total protein was measured using a biuret reagent. Glomerular expression of VEGF-A was evaluated by Western blot, mRNA for VEGF-A receptors in the renal cortex by RT-PCR. The vasoreactivity of the interlobar arteries to acetylcholine was assessed by wire myography. Long-term diabetes led to an increased concentration of VEGF-A, TAT, and urinary excretion of total protein and albumin, and a decrease in the concentration of sVCAM-1. We have shown that suramin in diabetes reduces total urinary protein excretion and restores the relaxing properties of acetylcholine relaxation properties to non-diabetic levels. Suramin had no effect on glomerular expression VEGF-A expression and specific receptors, and on sICAM-1 and nucleosomes concentrations in diabetic rats. In conclusion, the long-term effect of suramin on the kidneys in diabetes, expressed in the reduction of proteinuria and the restoration of endothelium-dependent relaxation of the renal arteries, can be considered as potentially contributing to the reduction/slowing down of the development of diabetic nephropathy.

Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors

Article

Nov 2023
CURR MED CHEM

Background Neglected tropical diseases are a severe burden for mankind, affecting an increasing number of people around the globe. Many of those diseases are caused by protozoan parasites in which cysteine proteases plays a key role in the parasite’s pathogenesis. Objective In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on activities such as the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain. Methods Exhaustive literature searches were performed using the keywords “Cysteine Proteases” and “Neglected Tropical Diseases” including the years 2017 - 2022. Overall, approximately 3’000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts. Conclusion Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitor’s potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Article

Full-text available

Oct 2023

Significance Statement African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. Background African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. Methods We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. Results In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. Conclusions APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

Genomic evidence of sex chromosome aneuploidy and infection-associated genotypes in the tsetse fly Glossina fuscipes, the major vector of African trypanosomiasis in Uganda

Article

Full-text available

Sep 2023

The primary vector of the trypanosome parasite causing human and animal African trypanosomiasis in Uganda is the riverine tsetse fly Glossina fuscipes fuscipes (Gff). Our study improved the Gff genome assembly with whole genome 10× Chromium sequencing of a lab reared pupae, identified autosomal versus sex-chromosomal regions of the genome with ddRAD-seq data from 627 field caught Gff, and identified SNPs associated with trypanosome infection with genome-wide association (GWA) analysis in a subset of 351 flies. Results from 10× Chromium sequencing greatly improved Gff genome assembly metrics and assigned a full third of the genome to the sex chromosome. Results from ddRAD-seq suggested possible sex-chromosome aneuploidy in Gff and identified a single autosomal SNP to be highly associated with trypanosome infection. The top associated SNP was ~1100 bp upstream of the gene lecithin cholesterol acyltransferase (LCAT), an important component of the molecular pathway that initiates trypanosome lysis and protection in mammals. Results suggest that there may be naturally occurring genetic variation in Gff in genomic regions in linkage disequilibrium with LCAT that can protect against trypanosome infection, thereby paving the way for targeted research into novel vector control strategies that can promote parasite resistance in natural populations.

FAZ assembly in bloodstream form Trypanosoma brucei requires kinesin KIN-E

Article

Aug 2023
MOL BIOL CELL

Trypanosoma brucei, the causative agent of African sleeping sickness, uses its flagellum for movement, cell division, and signaling. The flagellum is anchored to the cell body membrane via the flagellum attachment zone (FAZ), a complex of proteins, filaments, and microtubules that spans two membranes with elements on both flagellum and cell body sides. How FAZ components are carried into place to form this complex is poorly understood. Here, we show that the trypanosome-specific kinesin KIN-E is required for building the FAZ in bloodstream-form parasites. KIN-E is localized along the flagellum with a concentration at its distal tip. Depletion of KIN-E by RNAi rapidly inhibits flagellum attachment and leads to cell death. A detailed analysis reveals that KIN-E depletion phenotypes include failure in cytokinesis completion, kinetoplast DNA mis-segregation, and transport vesicle accumulation. Together with previously published results in procyclic form parasites, these data suggest KIN-E plays a critical role in FAZ assembly in T. brucei. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Phytochemical Analysis and Anti-trypanosomal Efficacy of the Methanol Leaf Extract of Jatropha curcas

Article

Full-text available

Sep 2022

Systematics of Trypanosomes of Medical and Veterinary Importance

Article

Full-text available

Jul 2004

This reference book includes comprehensive coverage of the biology and control of African, Asian and South American trypanosomiasis in man and animals. It describes recent research developments in the biology and molecular biology of trypanosomes and their vectors, and methods in diagnosis and control, such as tsetse trapping. Different sections of the book are devoted to biology of trypanosomes (part 1), vector biology (part 2), epidemiology and diagnosis (part 3), pathogenesis (part 4), disease impact (part 5), chemotherapy and disease control (part 6), and vector control (part 7). This book is intended for researchers in the areas of parasitology, medical and veterinary science, and biology, and for public health and veterinary staff and international agencies concerned with reducing mortality and morbidity due to trypanosomiasis.

The use of the sterile insect technique (SIT) for the eradication of the tsetse fly Glossina austeni (Diptera: Glossinidae) on the Island of Unguja (Zanzibar)

Article

Full-text available

Jan 2000
J ECON ENTOMOL

Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat

Article

Full-text available

Jan 2008
ANTIMICROB AGENTS CH

This study aimed to investigate if the absorption of the human African trypanosomiasis agent eflornithine was stereospecific and dose dependent after oral administration. Male Sprague-Dawley rats were administered single doses of racemic eflornithine hydrochloride as an oral solution (750, 1,500, 2,000, or 3,000 mg/kg of body weight) or intravenously (375 or 1,000 mg/kg of body weight). Sparse blood samples were obtained for determination of eflornithine enantiomers by liquid chromatography with evaporative light-scattering detection (lower limit of quantification [LLOQ], 83 microM for 300 microl plasma). The full plasma concentration-time profile of racemic eflornithine following frequent sampling was determined for another group of rats, using a high-performance liquid chromatography-UV method (LLOQ, 5 microM for 50 microl plasma). Pharmacokinetic data were analyzed in NONMEM for the combined racemic and enantiomeric concentrations. Upon intravenous administration, the plasma concentration-time profile of eflornithine was biphasic, with marginal differences in enantiomer kinetics (mean clearances of 14.5 and 12.6 ml/min/kg for L- and D-eflornithine, respectively). The complex absorption kinetics were modeled with a number of transit compartments to account for delayed absorption, transferring the drug into an absorption compartment from which the rate of influx was saturable. The mean bioavailabilities for L- and D-eflornithine were 41% and 62%, respectively, in the dose range of 750 to 2,000 mg/kg of body weight, with suggested increases to 47% and 83%, respectively, after a dose of 3,000 mg/kg of body weight. Eflornithine exhibited enantioselective absorption, with the more potent L-isomer being less favored, a finding which may help to explain why clinical attempts to develop an oral treatment have hitherto failed. The mechanistic explanation for the stereoselective absorption remains unclear.

Diamidines for human African trypanosomiasis

Article

Full-text available

Aug 2010

Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed.

NECT Is Next: Implementing the New Drug Combination Therapy for Trypanosoma brucei gambiense Sleeping Sickness

Article

Full-text available

May 2010
PLOS NEGLECT TROP D

Fatal if untreated, human African trypanosomiasis (HAT; sleeping sickness) afflicts an estimated 50,000–70,000 people each year [1], all in sub-Saharan Africa, with only a minority of cases (nearly 12,000 in 2008) being reported [2]. HAT is one of four neglected tropical diseases (NTDs) identified by the World Health Organization (WHO) as requiring Innovative and Intensified Disease Management (IDM), along with Chagas disease, leishmaniasis, and Buruli ulcer [3]. These particular NTDs have poorly understood burdens, lack optimal control tools, receive insufficient research and development (R&D) investment, and affect people who often live in remote or insecure areas with limited access to health care. Excluding Buruli ulcer, these IDM diseases have the highest death rates of all NTDs [4]. HAT in west and central Africa is caused by the protozoan parasite Trypanosoma brucei gambiense, transmitted through tsetse flies. The disease progresses from first stage (infecting blood and lymph) to second stage (infecting the central nervous system), which can lead to severe sleep disturbances, neurological and psychiatric disorders, coma, and death. Primary elements of HAT management are surveillance, diagnosis, treatment, and vector control. Drug treatments for T. b. gambiense HAT have been limited: pentamidine for first-stage disease, and melarsoprol or eflornithine for second-stage disease. Eflornithine is safer and often more effective than melarsoprol, which is associated with high toxicity, even fatal at times, and exhibits high rates of treatment failure in numerous HAT-endemic foci. However, despite an increasing proportion of second-stage HAT treated with eflornithine during recent years [5], melarsoprol remains in use in many treatment centers due to eflornithine's long, burdensome treatment administration requirements, which are difficult to implement in resource-constrained settings. In April 2009, a new treatment option, nifurtimox-eflornithine combination therapy (NECT), was added to the WHO Essential Medicines List (EML) for the treatment of second-stage T. b. gambiense HAT [6]. NECT was added to the EML based on the high efficacy and good safety profile observed in all studies done to date, against a background of recognized severity of stage 2 disease and toxicity of existing treatments. Surveillance of adverse events was strongly recommended [7]. Compared with eflornithine monotherapy, NECT is easier to administer and requires fewer human and material resources. In the current context, NECT stands as the most promising first-line treatment for second-stage T. b. gambiense HAT. Here we describe the developments and challenges in rolling out and implementing NECT in HAT-endemic areas.

Evaluation of the Cost-Effectiveness of Pyramidal, Modified Pyramidal and Monoscreen Traps for the Control of the Tsetse Fly, Glossina fuscipes fuscipes, in Uganda

Article

Full-text available

Sep 2007
J INSECT SCI

Several trap designs have been used for sampling and control of the tsetse fly, Glossina fuscipes fuscipes, Newstead (Diptera: Glossinidae) based on preferences of individual researchers and program managers with little understanding of the comparative efficiency and cost-effectiveness of trap designs. This study was carried out to evaluate the cost-effectiveness of four commonly used trap designs: monoscreen, modified pyramidal and pyramidal, relative to the standard biconical trap. The study was performed under high tsetse challenge on Buvuma Island, Lake Victoria, Uganda, using a 4 x 4 Latin square design replicated 3 times, so as to separate the trap positions and day effects from the treatment effect. A total of 12 trap positions were tested over 4 days. The monoscreen trap caught significantly higher numbers of G. f. fuscipes (P<0.05) followed by biconical, modified pyramidal and pyramidal traps. Analysis of variance showed that treatment factor was a highly significant source of variation in the data. The index of increase in trap catches relative biconical were 0.60 (pyramidal), 0.68 (modified pyramidal) and 1.25 (monoscreen). The monoscreen trap was cheaper (US

2.61) and required less material to construct than pyramidal trap (US

3.48), biconical and the modified pyramidal traps (US$ 4.06 each). Based on the number of flies caught per meter of material, the monoscreen trap proved to be the most cost-effective (232 flies/m) followed by the biconical trap (185 flies/m). The modified pyramidal and the pyramidal traps caught 112 and 125 flies/m, respectively.

How to Shorten Patient Follow-Up after Treatment for Trypanosoma brucei gambiense Sleeping Sickness

Article

Full-text available

Feb 2010
J INFECT DIS

BACKGROUND. Clinical management of human African trypanosomiasis requires patient follow-up of 2 years' duration. At each follow-up visit, cerebrospinal fluid (CSF) is examined for trypanosomes and white blood cells (WBCs). Shortening follow-up would improve patient comfort and facilitate control of human African trypanosomiasis. METHODS. A prospective study of 360 patients was performed in the Democratic Republic of the Congo. The primary outcomes of the study were cure, relapse, and death. The WBC count, immunoglobulin M level, and specific antibody levels in CSF samples were evaluated to detect treatment failure. The sensitivity and specificity of shortened follow-up algorithms were calculated. RESULTS. The treatment failure rate was 37%. Trypanosomes, a WBC count of > or = 100 cells/microL, and a LATEX/immunoglobulin M titer of 1:16 in CSF before treatment were risk factors for treatment failure, whereas human immunodeficiency virus infection status was not a risk factor. The following algorithm, which had 97.8% specificity and 94.4% sensitivity, is proposed for shortening the duration of follow-up: at 6 months, patients with trypanosomes or a WBC count of > or = 50 cells/microL in CSF are considered to have treatment failure, whereas patients with a CSF WBC count of > or = 5 cells/microL are considered to be cured and can discontinue follow-up. At 12 months, the remaining patients (those with a WBC count of > or = 6-49 cells/microL) need a test of cure, based on trypanosome presence and WBC count, applying a cutoff value of > or = 20 cells/microL. CONCLUSION. Combining criteria for failure and cure allows follow-up of patients with second-stage human African trypanosomiasis to be shortened to a maximum duration of 12 months.

Case Report- A rare case of human trypanosomiasis caused by Trypanosoma evansi

Article

Full-text available

Human trypanosoma infections like the ones seen in Africa and South America are unknown in India. The only exception in literature is of two documented cases of a self-limiting febrile illness, being attributed to Trypanosoma lewisi like parasites. We are reporting an unusual case of trypanosomiasis from the rural parts of Chandrapur district in Maharashtra. An adult male farmhand who used to practice veterinary medicine also, presented with history of febrile episodes on and off since five months and drowsiness before admission to this Institute. Though routine blood and other investigations were within normal limits, the peripheral smear showed a large number of trypanosomes which morphologically resembled the species Trypanosoma evansi , the aetiological agent of surra - a form of animal trypanosomiasis. A battery of assays covering the spectrum of parasitology, serology, and molecular biology confirmed the infecting parasite to be T. evansi . Failure to demonstrate the central nervous system (CNS) involvement, as evidenced by the absence of parasite in cerebrospinal fluid (CSF) advocated the use of suramin - the drug of choice in early stage African trypanosomiasis without any CNS involvement. Suramin achieved cure in our patient. The case is being reported because of its unique nature as the patient was not immunocompromised and showed infestation with a parasite which normally does not affect human beings.

Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial

Article

Full-text available

Jun 2009
LANCET

Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen. A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count </=20 cells per muL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations. The non-inferiority margin for the difference in cure rates was defined as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. One patient from the eflornithine group absconded after receiving the first dose, without any type of assessment done, and was excluded from all analyses. In the ITT population, 131 (91.6%) of 143 patients assigned to eflornithine and 138 (96.5%) of 143 patients assigned to NECT were cured at 18 months (difference -4.9%, one-sided 95% CI -0.3; p<0.0001). In the PP population, 122 (91.7%) of 133 patients in the eflornithine group and 129 (97.7%) of 132 in the NECT group were cured at 18 months (difference -6.0%, one-sided 95% CI -1.5; p<0.0001). Drug-related adverse events were frequent in both groups; 41 (28.7%) patients in the eflornithine group and 20 (14.0%) in the NECT group had major (grade 3 or 4) reactions, which resulted in temporary treatment interruption in nine and one patients, respectively. The most common major adverse events were fever (n=18), seizures (n=6), and infections (n=5) in the eflornithine group, and fever (n=7), seizures (n=6), and confusion (n=2) in the NECT group. There were four deaths, which were regarded as related to study drug (eflornithine, n=3; NECT, n=1). The efficacy of NECT is non-inferior to that of eflornithine monotherapy. Since this combination treatment also presents safety advantages, is easier to administer (ie, infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective against the emergence of resistant parasites, it is suitable for first-line use in HAT control programmes. Médecins Sans Frontières (Dutch section), Médecins Sans Frontières International, and the Drugs for Neglected Diseases Initiative.

Cardiac Alterations in Human African Trypanosomiasis (T.b. gambiense) with Respect to the Disease Stage and Antiparasitic Treatment

Article

Full-text available

Feb 2009
PLOS NEGLECT TROP D

In Human African Trypanosomiasis, neurological symptoms dominate and cardiac involvement has been suggested. Because of increasing resistance to the available drugs for HAT, new compounds are desperately needed. Evaluation of cardiotoxicity is one parameter of drug safety, but without knowledge of the baseline heart involvement in HAT, cardiologic findings and drug-induced alterations will be difficult to interpret. The aims of the study were to assess the frequency and characteristics of electrocardiographic findings in the first stage of HAT, to compare these findings to those of second stage patients and healthy controls and to assess any potential effects of different therapeutic antiparasitic compounds with respect to ECG changes after treatment. Four hundred and six patients with first stage HAT were recruited in the Democratic Republic of Congo, Angola and Sudan between 2002 and 2007 in a series of clinical trials comparing the efficacy and safety of the experimental treatment DB289 to the standard first stage treatment, pentamidine. These ECGs were compared to the ECGs of healthy volunteers (n = 61) and to those of second stage HAT patients (n = 56). In first and second stage HAT, a prolonged QTc interval, repolarization changes and low voltage were significantly more frequent than in healthy controls. Treatment in first stage was associated with repolarization changes in both the DB289 and the pentamidine group to a similar extent. The QTc interval did not change during treatment. Cardiac involvement in HAT, as demonstrated by ECG alterations, appears early in the evolution of the disease. The prolongation of the QTC interval comprises a risk of fatal arrhythmias if new drugs with an additional potential of QTC prolongation will be used. During treatment ECG abnormalities such as repolarization changes consistent with peri-myocarditis occur frequently and appear to be associated with the disease stage, but not with a specific drug.

The Natural Progression of Gambiense Sleeping Sickness: What Is the Evidence?

Article

Full-text available

Feb 2008
PLOS NEGLECT TROP D

Gambiense human African trypanosomiasis (HAT, sleeping sickness) is widely assumed to be 100% pathogenic and fatal. However, reports to the contrary exist, and human trypano-tolerance has been postulated. Furthermore, there is uncertainty about the actual duration of both stage 1 and stage 2 infection, particularly with respect to how long a patient remains infectious. Understanding such basic parameters of HAT infection is essential for optimising control strategies based on case detection. We considered the potential existence and relevance of human trypano-tolerance, and explored the duration of infectiousness, through a review of published evidence on the natural progression of gambiense HAT in the absence of treatment, and biological considerations. Published reports indicate that most gambiense HAT cases are fatal if untreated. Self-resolving and asymptomatic chronic infections probably constitute a minority if they do indeed exist. Chronic carriage, however, deserves further study, as it could seed renewed epidemics after control programmes cease.

The Burden of Human African Trypanosomiasis

Article

Full-text available

Feb 2008
PLOS NEGLECT TROP D

Human African trypanosomiasis (HAT, or sleeping sickness) is a protozoan parasitic infection caused by Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense. These are neglected tropical diseases, and T.b. rhodesiense HAT is a zoonosis. We review current knowledge on the burden of HAT in sub-Saharan Africa, with an emphasis on the disability-adjusted life year (DALY), data sources, and methodological issues relating to the use of this metric for assessing the burden of this disease. We highlight areas where data are lacking to properly quantify the impact of these diseases, mainly relating to quantifying under-reporting and disability associated with infection, and challenge the HAT research community to tackle the neglect in data gathering to enable better evidence-based assessments of burden using DALYs or other appropriate measures.

Trypanosomiasis vector control in Africa and Latin America

Article

Full-text available

Feb 2008

Vectors of trypanosomiasis - tsetse (Glossinidae) in Africa, kissing-bugs (Triatominae) in Latin America - are very different insects but share demographic characteristics that render them highly vulnerable to available control methods. For both, the main operational problems relate to re-invasion of treated areas, and the solution seems to be in very large-scale interventions covering biologically-relevant areas rather than adhering to administrative boundaries. In this review we present the underlying rationale, operational background and progress of the various trypanosomiasis vector control initiatives active in both continents.

Gonadotropic axis and Trypanosoma brucei gambiense infection

Article

Full-text available

Jul 1989

A gonad endocrine survey on 46 Congolese patients (15 women and 31 men) with parasitologically confirmed trypanosomiasis found amenorrhoea in 60% of the women and impotence in 70% of the men. The basic gonad endocrine examination showed a decrease in oestradiol levels in about 65% of the women. Both amenorrhoea and low oestrogen levels were observed in the second phase (P2) of the disease, but low oestrogen levels were sometimes noted in the first phase of the disease (P1). In the men, about 50% of the cases (P2) showed a decrease in testosterone. However, as in the women, the variation of testosterone was also observed in the first phase (P1). A static and dynamic examination of the hypothalamic-pituitary-gonadal axis was undertaken in order to investigate the origin of these hypogonadisms. A supra - or extra-hypophyseal origin is discussed.

Use of symptoms and signs for diagnosis of Trypanosoma brucei rhodesiense trypanosomiasis by rural health personnel

Article

Full-text available

Feb 1986
B WORLD HEALTH ORGAN

The results are described of a study of 60 patients with sleeping sickness from north-east Zambia together with 60 hospital controls and 27 nearest-neighbour controls. Eight symptoms were significantly commoner among sleeping-sickness patients than among either set of controls, and some of these symptoms were used to devise a scoring system for use by rural medical personnel. Although most patients reported a short history of the illness, almost 90% had abnormal cerebrospinal fluid, and there was a significant tendency for the cerebrospinal fluid of adults with a longer history of sleeping sickness to contain trypanosomes. Enlargement of lymph nodes was significantly more frequent among the patients than among the controls, but often the submandibular, axillary, or inguinal rather than the posterior cervical nodes were enlarged. Signs associated with involvement of the central nervous system were common, but the cheiro-oral reflex was non-specific, also occurring frequently among hospital controls.

Tsetse-flies (Glossinidae)

Article

Jan 1993

A.M. Jordan

Contribution à l'étude de la neurologie et neuropathologie de la trypanosomiase humaine

Article

Jan 1957

Clinical features of human African trypanosomiasis in children

Article

Jan 1977

Treatment of human trypanosomiasis

Article

Jan 1970

F. Apted

Human African trypanosomiasis (sleeping sickness): Epidemiological update

Article

Jan 2006

Handbook of Drugs for Tropical Parasitic Infections

Article

Dec 1988

Imported African Trypanosomiasis in the United States

Article

May 1975

Harrison C. Spencer

The trypanosome lytic factor of human serum and the molecular basis of sleeping sickness

Article

May 2004
Int J Parasitol

Luc Vanhamme

Trypanosoma brucei brucei infects a wide range of mammals but is unable to infect humans because this subspecies is lysed by normal human serum (NHS). The trypanosome lytic factor is associated with High Density Lipoproteins (HDLs). Several HDL-associated components have been proposed as candidate lytic factors, and contradictory hypotheses concerning the mechanism of lysis have been suggested. Elucidation of the process by which Trypanosoma brucei rhodesiense resists lysis and causes human sleeping sickness has indicated that the HDL-bound apolipoprotein L-I (apoL-I) could be the long-sought after lytic component of NHS. This research also allowed the identification of a specific diagnostic DNA probe for T. b. rhodesiense, and may lead to the development of novel anti-trypanosome strategies for use in the field.

Validité, coût et faisabilité de la mAECT et CTC comme tests de confirmation dans la détection de la Trypanosomiase Humaine Africaine

Article

Apr 2006

Resume Objectifs Evaluer la validité, le coût et la faisabilité de deux tests parasitologiques pour la confirmation de la maladie du sommeil; la mini Anion Exchange Centrifugation Technique (mAECT) et la Capillary Tube Centrifugation (CTC). Méthodes Au cours d'une campagne de dépistage de la maladie du sommeil en 2004 nous avons examiné 6502 personnes à Kwamouth en République Démocratique du Congo (RDC). Les personnes testées positives au Card Agglutination Test for Trypanosomiasis sur sang total (CATT) ont reçu une ponction ganglionnaire, un examen de sang frais, une goutte épaisse colorée, un examen de mAECT, un examen de CTC et une titration de CATT. La sensibilité et spécificité des tests de confirmation ont été calculées en utilisant la combinaison de tous les tests parasitologiques comme référence standard. Le coût de chaque méthode a été calculé et leur faisabilité a étéévaluée par des interviews structurées avec les techniciens. Résultats La sensibilité des méthodes parasitologiques classiques était de 44,8% (IC 95%: 36,8–53,0), pour la CTC 56,5% (IC 95%: 48,3–64,5) pour la mAECT 75,3 % (IC 95%: 67,7–81,9). Le coût par test était de 2,82€ pour la mAECT et 0,76€ pour la CTC. Le temps pour l'obtention du résultat était de 29,78 min pour la mAECT et 18,25 min pour la CTC. Ces deux tests ont été jugés faisables sous les conditions de terrain. Conclusion L'utilisation individuelle ou en combinaison de la CTC et de la mAECT comme tests de confirmation sur les personnes au CATT sur sang total apporterait une amélioration considérable de la détection des cas de trypanosomiase humaine africaine. Les deux tests se sont avérés faisables dans des conditions opérationnelles lorsque la disponibilité d'un courant de 220 V pouvait être garantie. Vue que le test mAECT est plus sensible mais considérablement plus coûteux, les analyses de coût‐efficacité de la faisabilité devraient guider au choix du meilleur algorithme.

Control and Surveillance of Human African Trypanosomiasis

Article

May 1999
T ROY SOC TROP MED H

J. R. Baker

Neuroendocrine Dysfunction in African Trypanosomiasis: The Role of Cytokinesa

Article

Feb 2006
ANN NY ACAD SCI

Sleeping sickness (SS; African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. Infection with Trypanosoma brucei in humans is associated with adynamia, lethargy, anorexia, and more specifically amenorrhea/infertility in women and loss of libido/impotence in men. Recent evidence suggests that experimental infection in animals with Trypanosoma brucei species causes polyglandular endocrine failure by local inflammation of the pituitary, thyroid, adrenal, and gonadal glands. In a cross-sectional study we investigated the prevalence and significance of neuroendocrine abnormalities in 137 Ugandan patients with SS. In the untreated stage of the disease, there was a high prevalence of adrenal insufficiency (27%), hypothyroidism (50%) and hypogonadism (85%). Pituitary function tests suggested an unusual combined central (hypothalamic/pituitary) and peripheral defect in hormone secretion. Specific therapy resulted in a rapid recovery of adrenal/thyroid function, whereas hypogonadism persisted for years in a substantial portion of patients. We did not detect pituitary, thyroid, adrenal, and gonadal autoantibodies in patients with endocrine dysfunction, ruling out an autoimmune origin of the endocrine abnormalities. However, the presence of hypopituitarism correlated with high cytokine concentrations (TNF-alpha, IL-6) which-together with direct parasitic infiltration of the endocrine glands-are involved in the pathogenesis of SS-associated endocrine dysfunction.

Efficience de différentes stratégies de détection de la Trypanosomiase Humaine Africaine àT. b. gambiense

Article

Apr 2005
TROP MED INT HEALTH

INTRODUCTION: Population screening for human African trypanosomiasis (HAT) is often based on a combination of two screening tests: lymph node palpation (LN) and card agglutination test for trypanosomiasis (CATT). This decision analysis compared the efficiency of three alternative detection strategies: screening by LN only, CATT only and their combination (LN and CATT). METHOD: An HAT detection strategy was defined as the sequence of screening and confirmation. Efficacy was evaluated in terms of lives saved. The cost of screening and confirmation tests was estimated in US

. The different parameters in the decision tree were based on published literature and observations of the HAT control programme in the Democratic Republic of Congo. A sensitivity analysis was carried out on those parameters subject to uncertainty. RESULTS: The cost-effectiveness of a detection strategy based on CATT was US

125 per life saved, compared with US

517 for LN and US

452 for the combined. Marginal cost to add LN to CATT only was between US

1225 and US

5000 per life saved. Sensitivity analysis shows that these results are robust to variation. DISCUSSION: The CATT strategy was the most efficient. None of the strategies was able to avoid more than 60% of HAT deaths. This moderate efficacy is due to the low sensitivity of the confirmatory (diagnostic) tests. Substantial efficiency gains can be obtained by adopting a CATT only strategy and resources can be better allocated to more sensitive confirmatory tests or to increasing the coverage of populations at risk.

Public-private partnership works to stamp out sleeping sickness in Uganda

Article

May 2007
Trends Parasitol

John David Kabasa

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[Detection of trypanosomes in blood by the Quantitative Buffy Coat (QBC) technique: experimental evaluation]

Article

Jan 1997
Med Trop

Microhematocrit centrifugation (Woo test) and miniature anion exchange are the most widely used techniques for routine detection of Trypanosoma brucei gambiense in endemic areas. The QBC technique developed for diagnosis of malaria has been successfully used for detection of trypanosoma in blood. The purpose of this laboratory study was to evaluate the end-point sensitivity of the QBC test in comparison with the Woo test. Decreasing concentrations from 15 x 10(5) to 15 trypanosomes/ml of human blood were tested using the two techniques. Sensitivity was calculated in function of reading time at each concentration. Results showed that the sensitivity of the QBC test was 95% down to a concentration of 450 trypanosomes/ml. In comparison 95% sensitivity of the Woo test was observed only down to 7500 trypanosomes/ml and reading time was twofold longer. These findings were reproducible for two hours after sample preparation but deterioration was rapid thereafter. Given its simplicity and sensitivity, QBC test would appear to be a suitable technique for in-field screening programs for human African trypanosomiasis.

Chemotherapy of second-stage Human African trypanosomiasis

Article

Aug 2010

Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy. To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis. We searched the Cochrane Infectious Diseases Group Specialized Register (May 2010), CENTRAL (The Cochrane Library Issue 3 2010) , MEDLINE (1966 to May 2010), EMBASE (1974 to May 2010), LILACS (1982 to May 2010 ), BIOSIS (1926-May 2010), mRCT (May 2010) and reference lists. We contacted researchers working in the field and organizations. Randomized and quasi-randomized controlled trials. Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI). Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. Fixed 10-day regimens of melarsoprol were found to be as effective as those of 26 days, with similar numbers of adverse events. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the burden on health personnel and patients, when compared to eflornithine monotherapy. Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.

African trypanosome infections of the nervous system: Parasite entry and effects on sleep and synaptic functions

Article

Dec 2009

The extracellular parasite Trypanosoma brucei causes human African trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes are transmitted by tsetse flies and HAT occurs in foci in sub-Saharan Africa. The disease, which is invariably lethal if untreated, evolves in a first hemo-lymphatic stage, progressing to a second meningo-encephalitic stage when the parasites cross the blood-brain barrier. At first, trypanosomes are restricted to circumventricular organs and choroid plexus in the brain outside the blood-brain barrier, and to dorsal root ganglia. Later, parasites cross the blood-brain barrier at post-capillary venules, through a multi-step process similar to that of lymphocytes. Accumulation of parasites in the brain is regulated by cytokines and chemokines. Trypanosomes can alter neuronal function and the most prominent manifestation is represented by sleep alterations. These are characterized, in HAT and experimental rodent infections, by disruption of the sleep-wake 24h cycle and internal sleep structure. Trypanosome infections alter also some, but not all, other endogenous biological rhythms. A number of neural pathways and molecules may be involved in such effects. Trypanosomes secrete prostaglandins including the somnogenic PGD2, and they interact with the host's immune system to cause release of pro-inflammatory cytokines. From the sites of early localization of parasites in the brain and meninges, such molecules could affect adjacent brain areas implicated in sleep-wakefulness regulation, including the suprachiasmatic nucleus and its downstream targets, to cause the changes characteristic of the disease. This raises challenging issues on the effects of cytokines on synaptic functions potentially involved in sleep-wakefulness alterations.

Cardiac involvement in African and American trypanosomiasis

Article

Nov 2008
LANCET INFECT DIS

American trypanosomiasis (Chagas disease) and human African trypanosomiasis (HAT; sleeping sickness) are both caused by single-celled flagellates that are transmitted by arthropods. Cardiac problems are the main cause of morbidity in chronic Chagas disease, but neurological problems dominate in HAT. Physicians need to be aware of Chagas disease and HAT in patients living in or returning from endemic regions, even if they left those regions long ago. Chagas heart disease has to be taken into account in the differential diagnosis of cardiomyopathy, primarily in patients with pathological electrocardiographic (ECG) findings, such as right bundle branch block or left anterior hemiblock, with segmental wall motion abnormalities or aneurysms on echocardiography, and in young patients with stroke in the absence of arterial hypertension. In HAT patients, cardiac involvement as seen by ECG alterations, such as repolarisation changes and low voltage, is frequent. HAT cardiopathy in general is benign and does not cause relevant congestive heart failure and subsides with treatment. We review the differences between the American and African trypanosomiasis with the main focus on the heart.

The epidemiology of sleeping sickness in the historical Luangwa Valley

Article

Feb 1977

H Buyst

This paper outlines the prehistorical and historical background of trypanosomiasis in Africa, with special reference to the Luangwa valley. It is thought that the haphazard contact of early man with flies of the G. fusca and G. morsitans groups led to his insusceptibility to T. brucei strains in a forest and woodland savannah ecology, while the more frequent contact with flies of the G. palpalis group caused him to retain his susceptibility to T. brucei strains of a river lake ecosystem. In the G. morsitans surroundings of the Luangwa valley human infective trypanosome strains could only manifest themselves after the arrival of (Ba-)ntu speaking people some 2,000 years ago had led to increased population densities. In more recent years the most outstanding epidemiological phenomenon has been a slow recovery of the Luangwa fly belt after the 1896 Rinderpest epidemic. Three main reasons are given for the occurrence of epidemic sleeping sickness in the endemic Luangwa valley. One of these is 'the collision of an expanding fly belt with the human habitat'. Another factor is that climatic stresses and a lack of game animals on the northern edge of the Luangwa fly belt force tsetse flies to feed more often on man. Finally, game movements cause tsetse flies to thrive and greatly increase in number during the rainy season in the same areas, where they starve, accumulate near villages and heavily depend on man during the dry season. The significance of subacute T. rhodesiense sleeping sickness in Zambia and other southeastern G. morsitans belts is elaborated. Its origin is believed to lie in a selection by man-infective trypanosome strains of people who are able to develop a more efficient immune response against them. That is why, in general, Europeans and Nilotes (e.g. in south-west Ethiopia) follow an acute course while the Bantu (e.g. in Zambia, Rhodesia and south-east Tanzania) usually follow a more subacute course of the disease. (Ba-)-ntu speaking people have a long history of almost uninterrupted contact with tsetse flies and, presumably, man-infective trypanosomes.

Trypanosoma brucei: Miniature anion-exchange centrifugation technique for detection of low parasitaemias: Adaptation for field use

Article

Feb 1979

The miniature anion-exchange/centrifugation (AEC) method, originally developed for the detection of submicroscopic trypanosomaemias in laboratory rodents, has been adapted for the diagnosis of trypanosomiasis in man in the field using blood samples obtained by finger-prick. It has been tested in a survey in The Gambia. The method is shown to be highly sensitive and to fulfil the first essential criteria for exploitation in the field, namely, that it can be operated in the open air under tropical conditions, and that an adequate number of subjects can be examined in a normal working day at an acceptable cost. The method also offers two advantages over the other highly sensitive method applicable to small blood samples, the microhaematocrit buffy-coat microscopy (MBCM) method, namely, that it minimizes the requirements for highly critical microscopy and provides, in the same operation, samples of diluted plasma which can be used for serological study.

A card-agglutination test with stained trypanosomes (C.A.T.T.) for the serological diagnosis of T. B. gambiense trypanosomiasis

Article

Feb 1978

A card-agglutination test (C.A.T.T.) has been developed for the serological diagnosis of T. b. gambiense trypanosomiasis. The antigen consists of a suspension of fixed and stained bloodstream trypanosomes of defined variable antigen type. The method has been evaluated by testing sera from 155 patients with proven T. b. gambiense infection, sera from 247 individuals free of sleeping sickness and sera from 54 patients with various parasitoses.

Imported African trypanosomiasis in the United States

Article

Jun 1975

Since 1967, six cases of African trypanosomiasis have been diagnosed and treated in the United States. Five patients were Americans infected with Trypanosoma rhodesiense, and the other was an African student with T. gambiense. Presenting signs and symptoms for all cases were typical of the disease, but often the diagnosis was delayed. The five Americans had spent only brief periods in endemic areas. All cases responded to therapy although one relapsed. Cases of imported sleeping sickness are few, and the risk of Americans acquiring the disease while traveling to endemic areas is low. However, the early diagnosis of sleeping sickness requires that physicians be cognizant of the possibility of imported tropical diseases.

Electrocardiographic changes in African trypanosomiasis caused by Trypanosoma brucei rhodesiense

Article

Feb 1975

The electrocardiographic findings in 40 patients with Trypanosoma brucei rhodesiense infection are reported. Using rigid diagnostic criteria 7 out of 18 patients (39%) had abnormal electrocardiograms before any form of therapy and 22 of the 40 patients (55%) had abnormal electrocardiograms at some stage of the disease or its treatment. The electrocardiographic abnormalities are described and discussed and the literature is reviewed.

Absence of the LiTat 1.3 (CATT antigen) gene in Trypanosoma brucei gambiense stocks from Cameroon

Article

Jul 1992
ACTA TROP

Antibodies to the variable antigen type (VAT) designated LiTat 1.3 are common in sera from parasitologically confirmed patients with gambian sleeping sickness. For this reason, LiTat 1.3 has been considered a suitable antigen for detecting Trypanosoma brucei gambiense in the Card Agglutination Test for Trypanosomiasis (CATT; Testryp-CATT, Smith Kline-RIT). However, surveys in the T.b. gambiense endemic focus of Fontem in Cameroon have suggested that expression of LiTat 1.3 might be rare or absent. We show here that the gene for LiTat 1.3 was indeed absent from some T.b. gambiense stocks isolated from this focus, and a LiTat 1.3-like gene was present in others. The divergent gene differed from the cloned version of LiTat 1.3. In addition, antibodies to LiTat 1.3 could not be detected in rabbits infected with either of the two kinds of T.b. gambiense from the Fontem area. We suggest that the absence of LiTat 1.3 expression in this focus may have important implications for the epidemiology and control of sleeping sickness, especially if heavy reliance is placed on the CATT.

High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire

Article

May 1992

Thirty patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with high-dose nifurtimox (30 mg/kg/d for 30 d). During treatment, the cerebrospinal fluid (CSF) white blood cell (WBC) count decreased in all patients except one (mean CSF WBC count before nifurtimox: 117/mm3; after nifurtimox: 25/mm3), and trypanosomes disappeared from the CSF of all 9 patients in whom parasites had been demonstrated before nifurtimox. Among 25 patients seen at least once after treatment, 9 (36%) have relapsed so far. High-dose nifurtimox was significantly toxic: one patient died during treatment and 8 others developed adverse neurological effects. High-dose nifurtimox seems more effective than the previously used regimen (15 mg/kg/d for 60 d), but at the expense of significant toxicity.

Diagnosis of human African trypanosomiasis

Article

Feb 1992

N Van Meirvenne

Human African trypanosomiasis or sleeping sickness is an endemic disease in many sub-Saharan countries. The causative agent is the unicellular haemoflagellate parasite Trypanosoma brucei, which is cyclically transmitted through the saliva of blood sucking tsetse flies. The more chronic “Gambian” form of sleeping sickness, which evolves fatally over a period of several months or years, predominates in West and Central Africa. It is caused by trypanosomes of the subspecies T. b. gambiense. The more fulminant “Rhodesian” form, due to the morphologically identical T. b. rhodesiense, is merely found in East Africa, where a large variety of game and domestic animals act as reservoir hosts. This parasite, which sometimes strikes safari tourists, can kill the patient within weeks or months.

Human African Trypanosomiasis

Abstract

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