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Human African Trypanosomiasis
Abstract
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 transmission of the pathogen mainly occurs by the infected tsetse fly, Glossina spp., from its saliva to the bloodstream of the human [13] (Fig. 1). In humans, HAT is caused by two sub-species of the parasite known as T. brucei gambiense in central and western Africa and T. brucei rhodesiense in eastern and southern Africa [14,15]. T. brucei gambiense accounts for more than 95% of reported cases [16]. ...
... At the moment, treatment of early and late-stage HAT relies mainly on suramin, pentamidine, melarsoprol, and eflornithine (Fig. 2). The effectiveness of treatment is significantly influenced by the long duration of treatment and the side effects of these medications [14,34]. Drug administration via intramuscular or intravenous routes is another drawback. ...
... The researchers could enhance the antitrypanosomal activity of compound 11 via molecular modification into more potent derivatives 12 and 13 ( Fig. 6) that exhibited T. brucei EC50 values of 3.2 nM and 1.9 nM, respectively. On the basis of SAR analysis, replacing 3-Cl and/or 4-OMe with hydrogen(s) led to inactive compounds (14)(15)(16). The relative position of the chlorine and methoxy group was important for the activity since 5-chloro-2methoxy analog was inactive (17) (EC50 > 10000 nM). ...
Trypanosomiasis is caused by parasitic protozoan trypanosomes in vertebrates. T. cruzi and T. brucei are causative agents of Chagas disease (CD) and Human African Trypanosomiasis (HAT), respectively. These life-threatening diseases are a serious threat to public health, with considerable incidence in sub-Saharan African and continental Latin America countries. Although WHO validated mitigated number of HAT cases in Togo (June 2020) and Cote d'Ivoire (December 2020), serious efforts need to be performed for the elimination of the disease. Antigenic variation of trypanosomal parasites provides a major bottleneck for developing effective vaccines. In the absence of human vaccines or chemoprophylaxis, the control of trypanosomatid infections may be envisaged through the eradication of vectors, management of animal reservoirs, and chemotherapy. A small number of chemical agents are currently available for antitrypanosomal treatments, and most of them are associated with toxicity, lack of efficacy, and non-oral route of administration. Given the restricted applicability of current medications, numerous efforts have been made for the synthesis and biological evaluation of heterocyclic scaffolds as antitrypanosomal candidates. In light of the above considerations, we were prompted to describe chemical diversity within privileged 5-membered heterocycles (imidazoles, thiazoles, triazoles and tetrazoles) as antitrypanosomal agents. The main purpose of the study was to throw light on the structure-activity relationship (SAR) of the relevant structures. To capture the recent structural diversity within reported cases, small molecules that belonged to the recent 7-year period (2015-2021) have been discussed. The available medications have also been briefly reviewed.
... cruzi); Human African trypanosomiasis (HAT, also known as African sleeping sickness) caused by infection with two of the three subspecies of Trypanosoma brucei (T. brucei); and various forms of leishmaniasis, which are caused by infection from different species of Leishmania [15][16][17][18]. All three subspecies (T. ...
... brucei) is an extracellular metacyclic trypomastigote parasite that is transmitted by the biting of an infected tsetse fly (Glossina genus) and causes sleeping sickness only in sub-Saharan Africa [19]. There are two subspecies of T. brucei that cause different disease: the more common west African HAT caused by T. b. gambiense and the less common east African HAT caused by T. b. rhodesiense [16,20]. The tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected animal, such as wild or domestic cattle in the case of T. b. rhodesiense or human beings in the case of T. b. gambiense HAT. ...
... b. gambiense or T. b. rhodesiense) and disease stage (i.e., presence or absence of central nervous system involvement). Suramin (16), pentamidine (17), melarsoprol (18) and eflornithine (19) (Fig. 3) are the commercially available drugs used for the treatment of African Trypanosomiasis. Table 1 shows the mechanism of action, dosages and related adverse effect of the drugs used against trypanosomatids. ...
Naphthoquinone is a heterocyclic moiety whose natural derivatives are present as bioactive compounds in many plants and have stimulated a resurgence of interest in the past decades due to their wide range of pharmacological activities. Naphthoquinone agents have dynamic pharmacophore and privileged sub-structures in the chemistry of medicine. They have received much interest in drug discovery as trypanocidal because naphthoquinone and their derivatives revealed massive significance potential against the trypanosomes. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer exhibited useful trypanocidal activities. Some naphthoquinones have already been used commercially as an antiparasitic agent. Several naphthoquinones with diverse structural motifs have been synthesized and evaluated mainly against Trypanosoma cruzi and some studies have also been reported against Trypanosoma brucei and Trypanosoma evansi. This review summarized various mechanisms of action of naphthoquinone like reductive activation of quinone by the production of the semiquinone, generation of reactive oxygen species and free radicals such as superoxide anion radical and H2O2, and oxidative stress in the parasite. The information assembled in this review will help to understand the mechanism behind the activity and may also be useful to find the bio-efficacy of naphthoquinone compounds upon substitution against trypanosomatids.
... The African trypanosomes are protozoan blood parasites and mainly transmitted by tsetse fl ies of the genus Glossina. The diseases caused by these pathogenic protozoans are fatal and are called sleeping sickness in humans and nagana in domestic livestock (Brun et al., 2010). Human sleeping sickness is caused by two subspecies of Trypanosoma brucei namely: T. b. gambiense and T. b. rhodesiense (Brun et al., 2010). ...
... The diseases caused by these pathogenic protozoans are fatal and are called sleeping sickness in humans and nagana in domestic livestock (Brun et al., 2010). Human sleeping sickness is caused by two subspecies of Trypanosoma brucei namely: T. b. gambiense and T. b. rhodesiense (Brun et al., 2010). African animal trypanosomiasis is a disease complex caused by T. congolense, T. vivax, or T. brucei brucei, or a simultaneous infection with one or more of these trypanosomes. ...
Trypanocidal and cytotoxic effects of traditionally used medicinal plants of Ethiopia were evaluated. A total of 60 crude plant extracts were prepared from 30 plant species using CH2Cl2 and MeOH. Effect upon cell proliferation by the extracts, for both bloodstream forms of Trypanosoma brucei brucei and human leukaemia HL-60 cells, was assessed using resazurin as vital stain. Of all CH2Cl2 and MeOH extracts evaluated against the trypanosomes, the CH2Cl2 extracts from five plants showed trypanocidal activity with an IC50 value below 20 μg/mL: Dovyalis abyssinica (Flacourtiaceae), IC50 = 1.4 μg/mL; Albizia schimperiana (Fabaceae), IC50 = 7.2 μg/mL; Ocimum urticifolium (Lamiaceae), IC50 = 14.0 μg/mL; Acokanthera schimperi (Apocynaceae), IC50 = 16.6 μg/mL; and Chenopodium ambrosioides (Chenopodiaceae), IC50 = 17.1 μg/mL. A pronounced and selective killing of trypanosomes with minimal toxic effect on human cells was exhibited by Dovyalis abyssinica (CH2Cl2 extract, SI = 125.0; MeOH extract, SI = 57.7) followed by Albizia schimperiana (CH2Cl2 extract, SI = 31.3) and Ocimum urticifolium (MeOH extract, SI = 16.0). In conclusion, the screening of 30 Ethiopian medicinal plants identified three species with good antitrypanosomal activities and low toxicity towards human cells. Dovyalis abyssinica might be a promising candidate for phytotherapy of trypanosomiasis
... sleeping sickness) is a neglected tropical disease caused by two subspecies of Trypanosoma brucei that have evolved resistance to human serum: T. b. gambiense in West and Central Africa, T. b. rhodesiense in East Africa [3]. The parasites are transmitted through the bite of the hematophagous tsetse fly (Glossina spp.) [4]. Competent vectors include savannah, sylvatic, and riverine species. ...
... Given their peculiar biology, in particular the fact that they are viviparous, the tsetse flies have never established populations outside their natural habitat in tropical Africa; thus, HAT remained a disease of the rural poor, threatening the people at exposed outdoor sites such as river crossings, water collection points, or washing sites. The epidemics in the 1990s were caused mainly by T. b. gambiense in the war-ridden regions of Angola, the Democratic Republic of the Congo (DRC), and southern Sudan/northern Uganda [4]. The last T. b. rhodesiense outbreaks occurred in eastern Uganda and northern Malawi with cattle and wild mammals, respectively, acting as the potential reservoirs for human-pathogenic trypanosomes [5,6]. ...
After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 µM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030.
... Human African trypanosomiasis (HAT) is caused by protozoan parasites Trypanosoma brucei (T. brucei subspecies i.e., gambiense and rhodesiense) [13]. This fatal infection is a part of the Neglected Tropical Diseases (NTDs) group transmitted via the bite of infected tsetse flies. ...
... Nandikolla et al., demonstrated practical synthesis of 28 newer derivatives of 1,2,3-triazole analogues of IMPC (imidazo-[1,2-a]-pyridine-3-carboxamide) [50]. 1 H-NMR, 13 C-NMR, LCMS and elemental analysis techniques were employed to characterize all synthesized compounds. LORA and MABA assays were used to evaluate all substances for their anti-TB potential in vitro (low-oxygen recovery assay (LORA): non-replicating; microplate Alamar blue assay (MABA): replicating M. tuberculosis). ...
People from low-income countries are increasingly affected by neglected communicable diseases, and the health care system frequently overlooks their needs. Currently, these diseases are known as Diseases of Neglected Populations (DNPs). Considering evolving threats of resistant strains of Plasmodium spp. and Mycobacteria, it is highly essential to search for newer drugs with new mechanisms of action. Imidazopyridines (IMPs) have been recognized as a privileged scaffold and have tremendous biological potential against varieties of anti-tubercular, anti-malarial and anti-trypanosomal targets. Our literature analysis suggested that IMPs have a mode of action via T. brucei farnesyl diphosphate synthase (TbFPPS), antimalarial kinase inhibition and enoyl acyl reductase inhibitions to act as anti-trypanosomal, antimalarial and anti-TB agents, respectively. Our result also found that IMPs are not fully explored against Trypanosomal and Plasmodium parasites. The present review highlights the medicinal significance of imidazopyridines for their rationale development as lead molecules with improved therapeutic efficacies against selected Diseases of Neglected Populations.
... This decline could be an underestimation due to lack of adequate diagnostic tools, technical and infrastructural deficiencies, poor accessibility and political instability in trypanosomiasis endemic areas (Berrang, 2007). (Brun et al., 2010). ...
... Current control approaches include the use of insecticides, spraying of land and livestock, sterile insect technique, paratransgenesis, traps and targets as well as the 'push-pull' method (Brun et al., 2010). ...
Tsetse flies are the sole vectors of Human African trypanosomiasis (sleeping sickness) and Animal African trypanosomiasis (Nagana). The insect is attracted to its suitable hosts through external signals which are perceived by olfactory receptors (ORs); thus representing the basis of transmission of the disease to thousands of people and millions of livestock. A developing approach to efficiently identify the key chemical ligands of odorant receptors entails expressing single ORs in different cell systems for consequent screening analysis. This study aimed to establish the expression of an expanded olfactory receptor family, Or67d of Glossina fuscipes fuscipes, a vector of both animal and human trypanosomiasis, in a Drosophila system. The receptor homologue is known to mediate responses to Drosophila melanogaster male-specific pheromone 11-cis-vaccenyl acetate (cVA) regulating mating behavior of males and females. In G. f. fuscipes, five copies of the same gene were found to be homologous to Or67d of Drosophila melanogaster. Out of the five copies, four were typically complete and only three of them contained the conserved seven-transmembrane- helix 6 (7tm_6) odorant receptor domain. Phylogenetic reconstruction of the four gene copies suggested a closest relationship between GffOr67d4 and Drosophila homolog, DmelOr67d. This gene copy was synthesized in pUC57 vector, amplified by polymerase chain reaction, cloned in pENTRTM/D-TOPO® vector then sub-cloned into the destination vector pTW. Sequencing analysis using Bioedit v.7.2.5.0 revealed that the gene was successfully cloned between attB sites, downstream of the upstream activating sequence (UAS). Afterwards, the recombinant plasmid was injected in Drosophila embryos by fly genetic services. Transgenic flies presenting red eyes were subjected to RNA extraction, cDNA synthesis and RT-qPCR analysis. All RT-qPCR performed on the Drosophila transgenic flies both males and females showed that our gene of interest GffOr67d4 was expressed in Drosophila relative to the internal control, alpha-tubulin. Our study revealed that the Drosophila system can actually be used as a heterologous cell system for the identification of behavioral and ecologically relevant chemical signals of ORs in tsetse fly species and for the design of olfactory-based strategies to control trypanosomiasis.
... These mVSGs represent the first and primary antigenic surface that is presented to the mammalian host immune system, an interaction that initially is focused on Th1 (pro-inflammatory type 1) cytokines, neutrophils and NK cell reactions to pathogen-associated molecular patterns (PAMPs), followed by T-cell independent IgM antibody activity. [25][26][27][28][29]. ...
During infection of mammalian hosts, African trypanosomes thwart immunity using antigenic variation of the dense Variant Surface Glycoprotein (VSG) coat, accessing a large repertoire of several thousand genes and pseudogenes, and switching to antigenically distinct copies. The parasite is transferred to mammalian hosts by the tsetse fly. In the salivary glands of the fly, the pathogen adopts the metacyclic form and expresses a limited repertoire of VSG genes specific to that developmental stage. It has remained unknown whether the metacyclic VSGs possess distinct properties associated with this particular and discrete phase of the parasite life cycle. We present here three novel metacyclic form VSG N-terminal domain crystal structures (mVSG397, mVSG531, and mVSG1954) and show that they mirror closely in architecture, oligomerization, and surface diversity the known classes of bloodstream form VSGs. These data suggest that the mVSGs are unlikely to be a specialized subclass of VSG proteins, and thus could be poor candidates as the major components of prophylactic vaccines against trypanosomiasis.
... It is made (Benoit et al. 2015). There are limited strategies of trypanosomiasis management primarily resulting from undesirable side effects of trypanocidal drug treatments; and there are emerging reports of multi-drug resistance (Barrett et al. 2007;Brun et al. 2010). According to the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC), eradicating tsetse populations is the most viable approach of controlling trypanosomiasis in sub-Sahara Africa (Solano et al. 2010). ...
Mutualism between endogenous viruses and eukaryotes is still poorly understood. Whole genome data has highlighted the diverse distribution of viral sequences in several eukaryote host genomes. A group of endogenous double-stranded polydnaviruses known as bracoviruses has been identified in parasitic braconid wasp (Hymenoptera). Bracoviruses allow wasps to reproductively co-opt other insect larvae. Bracoviruses are excised from the host genome and injected in to the larva along side the wasp eggs; where they encode proteins that lower host immunity allowing development of parasitoid wasp larvae in the host. Interestingly, putative bracoviral sequences have recently been detected in the first sequenced genome of the tsetse fly (Diptera). This is peculiar since tsetse flies do not share this reproductive lifestyle. To investigate genome rearrangements associated with these unique mutual symbiotic relationships and examine its value as a potential vector control strategy entry point. We use comparative genomics to determine the presence, prevalence and genetic diversity of bracoviruses of five tsetse fly species (G. austeni, G. brevipalpis, G. f. fuscipes, G. m. morsitans and G. pallidipes) and the housefly (Musca domestica). We identify and use four viral Maverick genes as evolutionary models for bracoviruses. This is the first record of homologous bracoviruses in multiple Dipteran genomes. Phylogenetic reconstruction of each gene revealed two major clades that represent the two types of Mavericks. We detect varying magnitudes of purifying selection across these loci except for the poxvirus A32 gene, which is under positive selection. Moreover, these genes were inserted at conserved regions and co-evolve at similar rates with the host genomes.
... Suramin or pentamidine used for HAT must be administered by injection for a prolonged period, and both carry the risk of adverse events. Melarsoprol, which may cause an encephalopathic syndrome that is fatal in up to 1 in 20 individuals taking the drug, remains the treatment of choice for Trypanosoma brucei rhodesiense HAT (9,10). Moreover, the emergence of drug resistance presents an obstacle to disease control (11,12). ...
Trypanosoma brucei , the pathogen causing African sleeping sickness (trypanosomiasis) in humans, causes debilitating diseases in many regions of the world, but mainly in African countries with tropical and subtropical climates. Enormous efforts have been devoted to controlling trypanosomiasis, including expanding vector control programs, searching for novel anti-trypanosomial agents, and developing vaccines, but with limited success. In this study, we systematically investigated the effect of graphene quantum dots (GQDs) on trypanosomal parasites and their underlying mechanisms. Ultrasmall-sized GQDs can be efficiently endocytosed by T. brucei and with no toxicity to mammalian-derived cells, triggering a cascade of apoptotic reactions, including mitochondrial disorder, intracellular reactive oxygen species (ROS) elevation, Ca ²⁺ accumulation, DNA fragmentation, adenosine triphosphate (ATP) synthesis impairment, and cell cycle arrest. All of these were caused by the direct interaction between GQDs and the proteins associated with cell apoptosis and anti-oxidation responses, such as trypanothione reductase (TryR), a key protein in anti-oxidation. GQDs specifically inhibited the enzymatic activity of TryR, leading to a reduction in the antioxidant capacity and, ultimately, parasite apoptotic death. These data, for the first time, provide a basis for the exploration of GQDs in the development of anti-trypanosomials.
... Both forms of the disease are considered lethal, if untreated [5], although long-term latent infections [6,7] and individuals clearing their infections without treatment have been described for gambiense HAT [8]. Given the severity and high case fatality of the disease, all detected cases should receive adequate treatment as early as possible after diagnosis. ...
Background:
Sleeping sickness, or human African trypanosomiasis (HAT), is transmitted by tsetse flies in endemic foci in sub-Saharan Africa. Because of international travel and population movements, cases are also occasionally diagnosed in non-endemic countries.
Methodology/principal findings:
Antitrypanosomal medicines to treat the disease are available gratis through the World Health Organization (WHO) thanks to a public-private partnership, and exclusive distribution of the majority of them enables WHO to gather information on all exported cases. Data collected by WHO are complemented by case reports and scientific publications. During 2011-2020, 49 cases of HAT were diagnosed in 16 non-endemic countries across five continents: 35 cases were caused by Trypanosoma brucei rhodesiense, mainly in tourists visiting wildlife areas in eastern and southern Africa, and 14 cases were due to T. b. gambiense, mainly in African migrants originating from or visiting endemic areas in western and central Africa.
Conclusions/significance:
HAT diagnosis in non-endemic countries is rare and can be challenging, but alertness and surveillance must be maintained to contribute to WHO's elimination goals. Early detection is particularly important as it considerably improves the prognosis.
... Proliferation occurs by binary fission accompanied with changes to a long, slender form, and acquisition of a coat of around 10 million molecules of identical, but variant, surface glycoproteins (VSG), which shield numerous membrane-associated transport proteins, necessary adaptations to residence in the bloodstream in close contact to the host immune effectors. The VSG coat protects the parasite from the human plasma lytic factors, a combination of apolipoprotein L1 and haptoglobin-related protein (Vanhamme and Pays, 2004;Brun et al., 2010). The proliferative, slender blood-stage trypomastigotes are observed during the onset of parasitaemia in blood, lymph, and spinal fluid. ...
Protozoan parasites induce severe diseases, world-wide prevalent such as toxoplasmosis, or widely spread in tropical and subtropical regions, affecting the poorest in developing countries, hence termed neglected tropical diseases. These are not uniquely due to protozoans, but are also induced by parasitic helminths, notably nematodes that are responsible for the most vicious diseases such as elephantiasis and river blindness, or debilitating infections of millions of children. The review is a reminder of the complexity of the pathogens life cycles, the dramatic prevalence of the diseases, the paucity, inefficiency, and toxicity of available drugs and therapies, and the almost entire lack of promising vaccines or prophylactic agents.
... T. brucei brucei is responsible for animal African trypanosomiasis, popularly known as nagana, which affects cattle, pigs, camels, sheep, and other animals. The main causative agents of human trypanosomiasis are T. brucei gambiense, responsible for more than 90% of cases in Africa (Simarro et al., 2010), and T. brucei rhodesiense, which can cause death if the host does not receive early diagnosis and treatment (Brun et al., 2010). ...
The Protist kingdom individuals are the most ancestral representatives of eukaryotes. They have inhabited Earth since ancient times and are currently found in the most diverse environments presenting a great heterogeneity of life forms. The unicellular and multicellular algae, photosynthetic and heterotrophic organisms, as well as free-living and pathogenic protozoa represents the protist group. The evolution of sex is directly associated with the origin of eukaryotes being protists the earliest protagonists of sexual reproduction on earth. In eukaryotes, the recombination through genetic exchange is a ubiquitous mechanism that can be stimulated by DNA damage. Scientific evidences support the hypothesis that reactive oxygen species (ROS) induced DNA damage can promote sexual recombination in eukaryotes which might have been a decisive factor for the origin of sex. The fact that some recombination enzymes also participate in meiotic sex in modern eukaryotes reinforces the idea that sexual reproduction emerged as consequence of specific mechanisms to cope with mutations and alterations in genetic material. In this review we will discuss about origin of sex and different strategies of evolve sexual reproduction in some protists such that cause human diseases like malaria, toxoplasmosis, sleeping sickness, Chagas disease, and leishmaniasis.
... Blood lymph and central nervous system (Brun et al., 2010;Nett et al., 2009) Leishmaniasis Leishmania Cutaneous, mucocutaneous or visceral (Reithinger et al., 2007;Torres-Guerrero et al., 2017) Giardia ...
Infectious outbreaks are the foremost global public health concern, challenging the current healthcare system, which claims millions of lives annually. The most crucial way to control an infectious outbreak is by early detection through point-of-care (POC) diagnostics. POC diagnostics are highly advantageous owing to the prompt diagnosis, which is economical, simple and highly efficient with remote access capabilities. In particular, utilization of nanomaterials to architect POC devices has enabled highly integrated and portable (compact) devices with enhanced efficiency. As such, this review will detail the factors influencing the emergence of infectious diseases and methods for fast and accurate detection, thus elucidating the underlying factors of these infections. Furthermore, it comprehensively highlights the importance of different nanomaterials in POCs to detect nucleic acid, whole pathogens, proteins and antibody detection systems. Finally, we summarize findings reported on nanomaterials based on advanced POCs such as lab-on-chip, lab-on-disc-devices, point-of-action and hospital-on-chip. To this end, we discuss the challenges, potential solutions, prospects of integrating internet-of-things, artificial intelligence, 5G communications and data clouding to achieve intelligent POCs.
... Trypanosoma brucei (T. brucei), is an extracellular bloodand tissue-borne protozoan parasite transmitted by Glossina (tsetse) fly vectors, which causes devastating diseases in humans, wild animals, and domesticated livestock (Brun et al., 2010). Human African trypanosomiasis (HAT, also known as African sleeping sickness) is a potentially fatal tropical disease found in remote rural regions of sub-Saharan Africa and often coincides with insubstantial health care systems (Fèvre et al., 2008). ...
African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei ( T. brucei ) and spread by the tsetse fly in sub-Saharan Africa. The trypanosome relies on heat shock proteins for survival in the insect vector and mammalian host. Heat shock protein 90 (HSP90) plays a crucial role in the stress response at the cellular level. Inhibition of its interactions with chaperones and co-chaperones is being explored as a potential therapeutic target for numerous diseases. This study provides an in silico overview of HSP90 and its co-chaperones in both T. brucei brucei and T. brucei gambiense in relation to human and other trypanosomal species, including non-parasitic Bodo saltans and the insect infecting Crithidia fasciculata . A structural analysis of T. brucei HSP90 revealed differences in the orientation of the linker and C-terminal domain in comparison to human HSP90. Phylogenetic analysis displayed the T. brucei HSP90 proteins clustering into three distinct groups based on subcellular localizations, namely, cytosol, mitochondria, and endoplasmic reticulum. Syntenic analysis of cytosolic HSP90 genes revealed that T. b. brucei encoded for 10 tandem copies, while T. b. gambiense encoded for three tandem copies; Leishmania major (L. major) had the highest gene copy number with 17 tandem copies. The updated information on HSP90 from recently published proteomics on T. brucei was examined for different life cycle stages and subcellular localizations. The results show a difference between T. b. brucei and T. b. gambiense with T. b. brucei encoding a total of twelve putative HSP90 genes, while T. b. gambiense encodes five HSP90 genes. Eighteen putative co-chaperones were identified with one notable absence being cell division cycle 37 (Cdc37). These results provide an updated framework on approaching HSP90 and its interactions as drug targets in the African trypanosome.
... Pathways processing extracellular signals are not conserved in phylogenetically distant kinetoplastids, including Trypanosoma 2,3 , and the connection of identified signaling components remains to be solved. Trypanosomes shuttle between mammalian and insect hosts and are well-studied due to medical and economic impact as causative agents of neglected tropical diseases in humans and animals 4 . A phenotype termed social motility (SoMo) 5 , a process similar to bacterial swarming 6 , indicates intercellular communication or peer signaling in populations of unicellular trypanosomes. ...
Signaling from ciliary microdomains controls developmental processes in metazoans. Trypanosome transmission requires development and migration in the tsetse vector alimentary tract. Flagellar cAMP signaling has been linked to parasite social motility (SoMo) in vitro, yet uncovering control of directed migration in fly organs is challenging. Here we show that the composition of an adenylate cyclase (AC) complex in the flagellar tip microdomain is essential for tsetse salivary gland (SG) colonization and SoMo. Cyclic AMP response protein 3 (CARP3) binds and regulates multiple AC isoforms. CARP3 tip localization depends on the cytoskeletal protein FLAM8. Re-localization of CARP3 away from the tip microdomain is sufficient to abolish SoMo and fly SG colonization. Since intrinsic development is normal in carp3 and flam8 knock-out parasites, AC complex-mediated tip signaling specifically controls parasite migration and thereby transmission. Participation of several developmentally regulated receptor-type AC isoforms may indicate the complexity of the in vivo signals perceived.
... More than 97% of the reported cases are due to T. b. gambiense, which causes a chronic form of the disease and is mostly found in west and central Africa. T. b. rhodesiense (eastern and southern Africa) causes an acute and fast-progressing form of the disease [2,3]. HAT has two stages: the first stage (hemolymphatic stage) begins when the Tsetse fly injects metacyclic trypomastigotes into the host's bloodstream. ...
Nitro-containing compounds are a well-known class of anti-infective agents, especially in the field of anti-parasitic drug discovery. HAT or sleeping sickness is a neglected tropical disease caused by a protozoan parasite, Trypanosoma brucei. Following the approval of fexinidazole as the first oral treatment for both stages of T. b. gambiense HAT, there is an increased interest in developing new nitro-containing compounds against parasitic diseases. In our previous projects, we synthesized several megazole derivatives that presented high activity against Leishmania major promastigotes. Here, we screened and evaluated their trypanocidal activity. Most of the compounds showed submicromolar IC50 against the BSF form of T. b. rhodesiense (STIB 900). To the best of our knowledge, compound 18c is one of the most potent nitro-containing agents reported against HAT in vitro. Compound 18g revealed an acceptable cure rate in the acute mouse model of HAT, accompanied with noteworthy in vitro activity against T. brucei, T. cruzi, and L. donovani. Taken together, these results suggest that these compounds are promising candidates to evaluate their pharmacokinetic and biological profiles in the future.
... Importantly, sleeping sickness is fatal if left untreated [1,2]. No vaccination exists and all available drugs are at best suboptimal [1,3,4]. This problem is further amplified by the fact that simple, accurate, and reliable diagnostic tests are by and large missing. ...
Human African Trypanosomiasis (HAT) is caused by the African trypanosome, a single-cell parasite that proliferates in the blood and cerebrospinal fluid of infected patients. Diagnostic measures for this pathogen are currently not sufficiently robust and reliable enough to permit effective disease control procedures. As a consequence, we suggested the development of a new sensor type, combining the selectivity of parasite-specific nucleic acid aptamers with the sensitivity of resonant electromagnetic devices to capture and detect the disease-causing organism. While we accomplished the detection of parasite cells in dehydrated specimens, here we summarize our recent progress toward electromagnetic sensors capable of uncovering parasites in liquid patient samples. We present a technique for the removal of blood cells from blood specimens and the deposition of trypanosome cells on glass microfiber membranes for dielectric spectrometry. Liquid suspensions of trypanosomes are characterized to determine the actual dielectric properties of single parasites and lastly, we present two sensor concepts optimized for the detection in liquids, along with a fabrication technique for the integration of microfluidic sample confinements.
... Agestandardised DALY rates for all causes decreased by 30·5% (95% UI 28·6-32·6) between 1990 and 2016 (appendix pp [49][50][51][52][53][54][55][56][57][58][59][60][61][62]. In 2016, CMNN causes accounted for 28·0% (26·4-29·7) of global DALYs, NCDs contributed 61·4% (59·4-63·2), and injuries contributed 10·7% (10·1-11·3; appendix pp [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. ...
... infections [1]. Trypanosoma brucei gambiense, T. brucei rhodesiense, and T. cruzi, along with 21 species of Leishmania, are pathogenic causes of human African trypanosomosis (HAT or sleeping sickness), Chagas disease (CD), and cutaneous (CL), mucocutaneous (MCL), or visceral (VL) leishmaniases [2][3][4][5], respectively. Occasional infections with T. evansi, T. lewisi, T. brucei brucei, or T. congolense have been reported in humans, but little is known about the public health importance of these diseases [6]. ...
Isothermal amplification of nucleic acids has the potential to be applied in resource-limited areas for the detection of infectious agents, as it does not require complex nucleic purification steps or specific and expensive equipment and reagents to perform the reaction and read the result. Since human and animal infections by pathogens of the Tryponasomatidae family occur mainly in resource-limited areas with scant health infrastructures and personnel, detecting infections by these methodologies would hold great promise. Here, we conduct a narrative review of the literature on the application of isothermal nucleic acid amplification for Trypanosoma and Leishmania infections, which are a scourge for human health and food security. We highlight gaps and propose ways to improve them to translate these powerful technologies into real-world field applications for neglected human and animal diseases caused by Trypanosomatidae.
... Most of them are discovered in the 1950s e.g., Melarsoprol is effective in the management of HAT, but it is utilization was restricted due to it is inconvenient side effect i.e., encephalopathy. Without any recommended drug for prophylaxis (Baker & Welburn, 2018;Blum et al., 2020;Brun et al., 2010;Thompson et al., 2018), there is a great requisite to produce novel oral, non-toxic, and effective medications for HAT, thus a lot of research has been done to find out new targets and effective treatments for this disease (Wall et al., 2018). ...
Human African Trypanosomiasis (HAT) or sleeping sickness is caused by the Trypanosoma brucei rhodesiense, a subspecies of the Trypanosomatide family. The parasite is associated with high morbidity and mortality rate in both animals and humans, claimed to be more fatal than other vector-transmitted diseases such as malaria. The majority of existing medications are highly toxic, not effective in the late chronic phase of the disease, and require maximum dosages to fully eradicate the parasite. In this study, we used computational methods to find out natural products that inhibit the Rhodesain, a parasitic enzyme that plays an important role in the parasite's pathogenicity, multiplication, and ability to pass through the host's blood-brain barrier. A library of 270540 natural products from ZINC databases was processed by using e-pharmacophore hypnosis and screening procedures, molecular docking, ADMET processes, and MM-GBSA calculations. This led to the identification of 3 compounds (ZINC000096269390, ZINC000035485292, and ZINC000035485242) which were then subjected to molecular dynamics. The findings of this study showed excellent binding affinity and stability toward the Rhodesain and suggest they may be a hopeful treatment for HAT in the future if further clinical trials were performed.
Communicated by Ramaswamy H. Sarma
... Human African trypanosomiasis takes 2 forms, depending on the subspecies of the parasite involved: Trypanosoma brucei gambiense is found in 24 countries in west and central Africa [7]. This form currently accounts for 97% of reported cases of sleeping sickness and causes a chronic infection [8,9]. ...
Background: The molecular mechanism of human African trypanosomiasis remains to be fully understood. It is urgently required to identify genes that are associated with trypanosome development and prognosis and to elucidate the underlying molecular mechanisms. In the present study, we aimed to identify potential pathogenic and prognostic differentially expressed genes (DEGs) associated with human trypanosomiasis through bioinformatics analysis of genetic profiles from infected patients. Methods: The gene expression dataset of trypanosome infected (GSE85996) patients were obtained from the Gene Expression Omnibus (GEO). DEGs were identified using the LIMMA Package of R. The GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were conducted through Enrich. The protein-protein interaction (PPI) network of the DEGs was established through the STRING (Search Tool for the Retrieval of Interacting Genes database) server. Results: A total of 20 differentially expressed genes including 3 upregulated genes (STAT1, FBXW17 and LRRC15), and 17 downregulated genes (Setbp1, Aldh1a2) were identified. The PPI network of the DEG identified a total of 40 nodes, 254 edges, 12.7 average node degree, and a PPI enrichment p-value of < 1.0e-16. The enriched KEGG pathway of the DEG includes; Relaxin signalling pathway, retinol metabolism, erbb signalling pathway, neuroactive ligand-receptor interaction, TNF signalling pathway, and focal adhesion. However, the enriched GO were r FGFR signalling pathway, cardiac endothelial cell differentiation, cardiac muscle cell myoblast differentiation, plasminogen activation, mast cell chemotaxis, endocardial cell differentiation, and transmembrane receptor protein tyrosine kinase. Conclusion: The present study may provide a basis for an improved understanding of trypanosome infection in humans. The DEGs identified in this study could be utilized as new biomarkers for prognosis and potential new targets for the development of new drugs against human trypanosomiasis.
... The more common form (98% of cases) occurs in West and Central Africa and is caused by Trypanosoma brucei gambiense (gHAT). The less common form (2% of cases) occurs in East and Southern Africa and is caused by Trypanosoma brucei rhodesiense (rHAT; Brun et al., 2010;Franco et al., 2020). Additionally, AAT is estimated to cost African agriculture USD 4.5 billion per year (Morrison et al., 2016) and therefore remains one of the main constraints for the development of livestock and agriculture in sub-Saharan Africa (Diall et al., 2017). ...
Sleeping sickness is still prevalent in Campo, southern Cameroon, despite the efforts of World Health Organization and the National Control Programme in screening and treating cases. Reducing disease incidence still further may need the control of tsetse vectors. We update entomological and parasitological parameters necessary to guide tsetse control in Campo. Tsetse flies were trapped, their apparent densities were evaluated as the number of flies captured per trap per day and mapped using GIS tools. Polymerase chain reaction based methods were used to identify their trypanosome infection rates. Glossina palpalis palpalis was the dominant vector species representing 93.42% and 92.85% of flies captured respectively during the heavy and light dry seasons. This species presented high densities, that is, 3.87, 95% CI [3.84–3.91], and 2.51, 95% CI [2.49–2.53] flies/trap/day in the two seasons. Moreover, 16.79% (of 1054) and 20.23% (of 1132 flies) were found infected with at least 1 trypanosome species for the 2 seasons respectively, Trypanosoma congolense being the most prevalent species, and Trypanosoma. brucei gambiense identified in 4 samples. Tsetse flies are abundant in Campo and present high trypanosome infection rates. The detection of tsetse infected with human trypanosomes near the newly created palm grove show workers' exposition. Tsetse densities maps built will guide vector control with ‘Tiny Targets’. High densities of tsetse fly vectors of Human sleeping sickness and animal trypanosomoses are recorded in the transborder focus of Campo, South Cameroon. Around 20% of these flies are infected with trypanosome parasites, among which Trypanosoma brucei gambiense, the human parasite. Population activities and new development projects implemented in the area (plantations creation, roads…) increase human exposure to tsetse bites and disease transmission risk, and therefore, vector control is needed.
... Microscopy is essential in diagnosing HAT since it detects motile trypanosomes and fixes and stained organisms in the bloodstream. Microscopy of spinal fluid must be done after a HAT diagnosis is made to see if the patient has reached the neurological stage of the illness, which is very important in deciding what kind of treatment the patient needs (Brun, Blum, Chappuis, & Burri, 2010). ...
... Adverse reactions are similar to eflornithine and include pancytopenia, GI distress and convulsions. Similarly, suramin and melarsoprol are utilized for the first-and second-stage treatment of disease caused by T. brucei rhodesiense, respectively [107,110]. ...
The parasitology refers to interactions between two organisms of different sizes in which the benefitted one is known as the parasite and the other one which suffers is called the host. Although there are numerous prokaryotic and eukaryotic parasites, the main emphasis is based upon those which are responsible for most deadly illness leading to cause millions of deaths and billions of infections in humans every year. Public health agencies and research organizations largely hire parasitologists to test therapies, prophylactics and vaccines that prevent parasitic infections. Parasites can develop drug resistance, so it is therefore necessary to understand their genes, proteins, life cycles and evolution through research to monitor infections and to predict potential outbreaks.
... The perceived low importance of sleeping sickness, new conflicts, and the challenge of building independent health systems led to a reduced effort to control trypanosomiasis; a subsequent slow but constant increase of cases resulted in an epidemic surge by the end of the 1980s. 6 Few international nongovernmental organizations were involved in HAT control activities-MSF being the most active of these-while the NSSCPs were poorly staffed and funded. At the turn of the twenty-first century, WHO developed a program to reduce disease transmission, reinforcing the NSSCPs and partnering with international stakeholders, including the two companies that produced all the drugs for HAT, Sanofi, and Bayer. ...
In this article, the authors show the strategy used to streamline the introduction of fexinidazole, the first all oral treatment of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense. The dose range was determined in phase 1 studies and a significant food effect was observed, which was tested with field-adapted meals. The pharmacokinetic profile required definition of a higher loading dosage for the first 4 days and administration of the daily dose together with a typical local meal to optimize product absorption and rapidly achieve drug steady state. This allowed for a combined phase II/III pivotal study directly after phase I trials. Partnerships with highly engaged actors from endemic country control programs and international research institutions started early through the HAT platform, building on an agreed target product profile (TPP), establishing a regulatory plan early and transparently including endemic countries in the research and data flow. A key element that enabled a quick start to access activities was preparing for World Health Organization guidelines early and starting the process prior to registration. Distribution plans were identified and supply was established from the start, by taking advantage of the existing supply agreement between the producers of all HAT drugs (Sanofi and Bayer) and the WHO. Pharmacovigilance and phase 4 studies were nested into wider implementation activities. Targeted sequential introduction into national programs was prioritized, based on medical need and epidemiologically updated information.
... HIBCPP cells on Transwell filters were used as a model of the blood-CSF barrier Transmigration efficiency of Trypanosoma brucei brucei was quantified by qPCR Transmigration seemed independent of major surface metalloprotease B Transmigration might be a mechanical process affected by parasite geometry/motility INTRODUCTION Human African trypanosomiasis (HAT) or sleeping sickness is an infectious disease caused by the unicellular eukaryotic flagellated parasite Trypanosoma brucei (Brun et al., 2010) that lives in blood, lymphatic system, and interstitial spaces of organs (Kennedy, 2013). These trypanosomes are transmitted by telmophagous blood-sucking tsetse flies (Lavoipierre, 1965) which are native in endemic areas in sub-Saharan Africa. ...
Trypanosoma brucei is the causative agent of Human African Trypanosomiasis. The parasite transmigrates from blood vessels across the choroid plexus epithelium to enter the central nervous system, a process that leads to the manifestation of second stage sleeping sickness. Using an in vitro model of the blood-cerebrospinal fluid barrier, we investigated the mechanism of the transmigration process. For this, a monolayer of human choroid plexus papilloma cells was cultivated on a permeable membrane that mimics the basal lamina underlying the choroid plexus epithelial cells. Plexus cells polarize and interconnect forming tight junctions. Deploying different T. brucei brucei strains, we observed that geometry and motility are important for tissue invasion. Using fluorescent microscopy, the parasite’s moving was visualized between plexus epithelial cells. The presented model provides a simple tool to screen trypanosome libraries for their ability to infect cerebrospinal fluid or to test the impact of chemical substances on transmigration.
... It is transmitted via the bite of the blood-sucking tsetse fly, which is a viviparous insect that deposits a fully developed larva, which then needs to become an adult fly and feeds on an infected mammalian host in order to evolve into the infective form. Only about 0-1% of flies carries a mature infection that can be transmitted to another host [45]. The early stage of the pathology is characterized by headaches, weight loss, fever, and lymphadenopathy, which evolve into more serious symptoms that potentially involve the nervous system when the parasite crosses the blood-brain barrier (BBB) [46], producing neurological disturbances including sleep disorder, tremor of the hands, and motor weakness, and can lead to death if untreated [47]. ...
Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided.
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... The HAT constitutes one of the most neglected tropical diseases (NTDs) with devastating health and economic consequences in sub-Sahara Africa, with most recent epidemic reported between 1990 and 2015 (Brun et al., 2010;Aksoy et al., 2017). Likewise, AAT is rampant in livestock inhabiting tsetse fly-infested areas throughout the continent. ...
Tsetse-transmitted trypanosomiases are among the most neglected tropical diseases in sub-Sahara Africa. Although all tsetse species are susceptible to trypanosome infections, their differential attraction/feeding preferences for different wildlife, domestic animals, and/or humans constitute critical determinants of trypanosomes species they predominantly transmit. Artificial bait technologies, based on long-range tsetse olfactory responses to natural cues emitted by preferred hosts and blends of synthetic versions that mimic these cues, have successfully been applied in attractant-odor-based (“pull” tactic) reduction of field populations of some tsetse species. Olfactory attribute associated with active avoidance of tsetse-refractory non-hosts has similarly been exploited in design of repellent-odor-based (“push” tactic) protection of livestock. These tactics have opened possibility of spatially strategic deployment of the two sets of odor baits in “push-pull” tactics. Possibility of developing blends with enhanced attraction and repellence compared with those associated with savannah tsetse fly hosts and non-hosts, respectively, have been explored, where structure activity and blends of different components generated two novel blends. The studies evaluated structure activity and blends of different components. One based on attractive constituents associated with buffalo ( Syncerus caffer ) comprised of ε-nonalactone, nonanoic acid, 2-nonanone (in 1:3:2 proportion) delivered together with acetone, which showed significantly better attractancy on savannah tsetse fly than the standard blend comprised of 3-propylphenol, octenol, p-cresol, and acetone (POCA). The other blend comprised of δ-nonalactone, heptanoic acid, 4-methylguaiacol and geranylacetone (in 6:4:2:1 proportion) was significantly more repellent than previously characterized blend based on tsetse fly refractory waterbuck ( Kobus defassa ) constituents (δ-octalactone, pentanoic acid, guaiacol and geranylacetone). So far, no effective attractants or repellents of riverine tsetse fly species have been characterized. Optimized attractant and repellent blends for savannah tsetse flies lay down useful groundwork for future development of the “push-pull” deployment tactic for area-wide control of tsetse flies. Better understanding of the physiological, cellular, and molecular basis of response in the tsetse fly to odors can potentially augment the current tsetse fly-control interventions.
... En effet, les orpailleurs pratiquent des activités à risque dans un environnement infesté par les mouches tsé-tsé (Somda et al., 2021), notamment l'orpaillage en priorité, l'agriculture, l'élevage et le commerce comme activités mineures. Des études ont montré que d'autres activités telles que la pêche, la coupe du bois, la natation et/ou la lessive au bord d'un cours d'eau, l'approvisionnement en eau dans un cours d'eau, le commerce en milieu rural, la chasse et l'extraction de sel, exposent plus les populations rurales à la THA (Brun et al., 2010;Courtin et al., 2015;Meda et al., 1993;Mpiana et al., 2015). De façon générale, les activités agricoles peuvent être des facteurs à risque de la maladie du sommeil, tout comme ils le sont pour le paludisme et les arboviroses qui sont également des maladies vectorielles (Mpiana et al., 2015;Sadia-Kacou et al., 2019;Yobo et al., 2018). ...
Une prospection médicale récente sur la trypanosomose humaine africaine (THA) dans des sites d'orpaillage au Sud-Ouest du Burkina Faso, a mis en évidence la présence de mouches tsé-tsé infectées et des populations venant de la Côte d'Ivoire et de la Guinée, les deux pays d'Afrique de l'Ouest les plus affectés par cette maladie. Cet état de fait, montre un risque de réémergence de cette maladie. L'objectif de cette étude était de recueillir les perceptions des populations vivant à proximité de ces sites d'orpaillage du Sud-Ouest du Burkina Faso afin de proposer des stratégies pour minimiser ce risque de réémergence de la THA. Pour ce faire une enquête sur les connaissances, attitudes et pratiques (CAP) a été réalisée en entretien semi-structuré auprès des personnes ressources, suivie des enquêtes CAP individuelles ciblant les orpailleurs dans la zone d'étude. Les résultats ont montré que les 29 personnes ressources sont peu informées sur la THA. Ce résultat a été confirmé par les CAP individuelles auprès des 130 orpailleurs enquêtés qui sont peu informés sur la THA : 87,69% sur ses modes de transmission, 78,46% sur ses symptômes et 100% sur les stratégies appropriées de gestion. A l'issue de cette étude, des recommandations ont été faites.
... Trypanosomatids are insect-borne parasites that cause fatal diseases such as Chagas' disease [96] or African trypanosomiasis, "the sleeping sickness" [97]. EVs secreted by trypanosomes were shown to increase virulence in various studies. ...
Extracellular vesicles (EVs) have lately emerged as crucial mediators in parasite infections. Recent research suggests that protozoan parasites, including Leishmania, employ EVs as transport vehicles to deliver biologically active effector molecules such as parasitic virulence factors to modulate the host immune system and their microenvironment. The immunomodulatory effects of EVs play an essential role in the formation and progression of parasitic diseases. The immunomodulatory strategies applied by EVs of protozoan origin have similarities to the development and progression of other infections or diseases such as cancer. In this chapter, we will provide recent insights into the role of EVs in host-pathogen interactions, intercellular-communication, immunomodulation and pathogenesis of Leishmania and other protozoan parasites, including Plasmodium spp., Toxoplasma spp. and Trypanosoma spp. In addition, biologically inspired by the immunomodulation strategies of protozoan parasites, new immunotherapeutic models are being currently investigated to implement EVs more intensively in both therapy and diagnostics. Therefore, besides highlighting the role of EVs in protozoan infections, this chapter sheds light briefly on new immunotherapeutic approaches utilizing the strategies of protozoan EVs in medicine.
... Of the two recognized forms of HAT, that caused by T. b. gambiense is endemic in western and central Africa, whereas that caused by T. b. rhodesiense occurs in eastern and southern Africa [3,5]. HAT cases are also detected among travellers, tourists and migrants outside the endemic countries of sub-Saharan Africa, including in the Americas, Europe and Asia [6]. ...
Background
In the 20th century, epidemics of human African trypanosomiasis (HAT) ravaged communities in a number of African countries. The latest surge in disease transmission was recorded in the late 1990s, with more than 35,000 cases reported annually in 1997 and 1998. In 2013, after more than a decade of sustained control efforts and steady progress, the World Health Assembly resolved to target the elimination of HAT as a public health problem by 2020. We report here on recent progress towards this goal.
Methodology/principal findings
With 992 and 663 cases reported in 2019 and 2020 respectively, the first global target was amply achieved (i.e. fewer than 2,000 HAT cases/year). Areas at moderate or higher risk of HAT, where more than 1 case/10,000 people/year are reported, shrunk to 120,000 km ² for the five-year period 2016–2020. This reduction of 83% from the 2000–2004 baseline (i.e. 709,000 km ² ) is slightly below the target (i.e. 90% reduction). As a result, the second global target for HAT elimination as a public health problem cannot be considered fully achieved yet. The number of health facilities able to diagnose and treat HAT expanded (+9.6% compared to a 2019 survey), thus reinforcing the capacity for passive detection and improving epidemiological knowledge of the disease. Active surveillance for gambiense HAT was sustained. In particular, 2.8 million people were actively screened in 2019 and 1.6 million in 2020, the decrease in 2020 being mainly caused by COVID-19-related restrictions. Togo and Côte d’Ivoire were the first countries to be validated for achieving elimination of HAT as a public health problem at the national level; applications from three additional countries are under review by the World Health Organization (WHO).
Conclusions/significance
The steady progress towards the elimination of HAT is a testament to the power of multi-stakeholder commitment and coordination. At the end of 2020, the World Health Assembly endorsed a new road map for 2021–2030 that set new bold targets for neglected tropical diseases. While rhodesiense HAT remains among the diseases targeted for elimination as a public health problem, gambiense HAT is targeted for elimination of transmission. The goal for gambiense HAT is expected to be particularly arduous, as it might be hindered by cryptic reservoirs and a number of other challenges (e.g. further integration of HAT surveillance and control into national health systems, availability of skilled health care workers, development of more effective and adapted tools, and funding for and coordination of elimination efforts).
... Trypanosomiasis and onchocerciasis are common diseases in sub-Saharan Africa and are specifically treated with suramin (Anderson et al., 1976;Cheson, et al., 1987;Barrett et al., 2007;Brun, 2010;Babokhov et al., 2013;Federica et al., 2016;Büscher et al., 2017). This market-approved anti-parasite medication was developed in 1921 and its pharmacological development was stimulated for its antitumor, antiinflammatory, and antiviral activities (Yahi et al., 1994;Liu. ...
A promising approach in cancer therapy is the inhibition of cell proliferation using small molecules. In this study, we report the synthesis of suramin derivatives and their applications. We used NMR spectroscopy and docking simulations to confirm binding sites and three-dimensional models of the ligand-protein complex. The WST-1 assay was used to assess cell viability and cell proliferation in vitro to evaluate the inhibition of protein–protein interactions and to investigate the anti-proliferative activities in a breast cancer cell line. All the suramin derivatives showed anti-proliferative activity by blocking FGF1 binding to its receptor FGFRD2. The dissociation constant was measured by fluorescence spectroscopy. The suramin compound derivatives synthesized herein show potential as novel therapeutic agents for their anti-proliferative activity via the inhibition of protein–protein interactions. The cytotoxicity of these suramin derivatives was lower than that of the parent suramin compound, which may be considered a significant advancement in this field. Thus, these novel suramin derivatives may be considered superior anti-metastasis molecules than those of suramin.
Background and objectives:
Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT.
Methods:
Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored.
Results:
Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg.
Conclusions:
This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT.
Trial registration:
The study was registered with ClinicalTrials.gov: NCT01533961.
The human African trypanosomiasis is a devastating parasitic infection, which is caused by the protozoan Trypanosoma brucei and transmitted by the bite of the tsetse fly. An untreated infection usually results in death and only few drugs with significant drawbacks are currently available for treatment. Previous investigations revealed the quinolone amide MB007 as a lead compound with an excellent selectivity for T. b. brucei. Here, new quinolone amides were synthesized for deeper insights into the structure-activity relationship. Furthermore, the aqueous solubility of the compounds was analyzed, as the poor solubility of previous quinolone amides impeded in vivo studies for target identification. The biological evaluation led to the new lead structure 9f, which exhibits a promising in vitro activity against T. b. brucei (IC50 = 22 nM) and showed no cytotoxicity against macrophages. Moreover, compounds 10b and 10c were discovered, which possessed an improved solubility combined with a decent selectivity.
Chagas disease and Human African Trypanosomiasis, caused by Trypanosoma cruzi and T. brucei, respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and TbrCatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC50 values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC50 values were obtained for six of them (hit rate = 1.5%) and ranged from 0.46 ± 0.03 to 27 ± 3 µM. MMV688246 was found to be a mixed inhibitor of cruzain (Ki = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (Ki = 165 ± 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and TbrCatL are of great interest for further optimization by the medicinal chemistry community.
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 flagellar 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 .
Flavonoids are a category of plant-derived compounds which exhibit a large number of health-related effects. One of the most well-known and studied flavonoids is kaempferol, which can be found in a wide variety of herbs and plant families. Apart from their anticarcinogenic and anti-inflammatory effects, kaempferol and its associated compounds also exhibit antibacterial, antifungal, and antiprotozoal activities. The development of drugs and treatment schemes based on these compounds is becoming increasingly important in the face of emerging resistance of numerous pathogens as well as complex molecular interactions between various drug therapies. In addition, many of the kaempferol-containing plants are used in traditional systems all over the world for centuries to treat numerous conditions. Due to its variety of sources and associated compounds, some molecular mechanisms of kaempferol antimicrobial activity are well known while others are still under analysis. This paper thoroughly documents the vegetal and food sources of kaempferol as well as the most recent and significant studies regarding its antimicrobial applications.
Principles of Medicine in Africa combines classical clinical medicine with a rich understanding of the major environmental and cultural influences on health and disease, providing comprehensive guidance for anyone intending to practise medicine in Africa. Disease is presented in the context of family and culture, and the effects of inequality and problems of limited resources are addressed. The authors have a wealth of experience in front line healthcare and provide practical, evidence-based management guidelines for all the common and less common conditions likely to be encountered. This fourth edition has been thoroughly updated to incorporate the latest research findings and management guidelines. It includes an expanded section on maternal and child health, but careful editing has generated a slimmer volume, whilst retaining all of the essential content. This is the one essential text for medical students and healthcare professionals wanting a complete and up-to-date reference book on medicine in Africa.
During infection of mammalian hosts, African trypanosomes thwart immunity using antigenic variation of the dense Variant Surface Glycoprotein (VSG) coat, accessing a large repertoire of thousands of genes and pseudogenes and switching to antigenically distinct copies. The parasite is transferred to mammalian hosts through the bite of the tsetse fly. In the salivary glands of the fly, the pathogen adopts the metacyclic form and expresses a limited repertoire of VSG genes specific to that developmental stage. It has remained unknown whether the metacyclic VSGs possess distinct properties associated with this particular and discrete phase of the parasite life cycle. We show here using bioinformatic, crystallographic, and immunological analyses of three metacyclic VSGs that they closely mirror the known classes of bloodstream form VSGs both in structure and in the immunological responses they elicit.
The primary vector of the trypanosome parasite causing human and animal African trypanosomiasis in Uganda is the riverine tsetse fly Glossina fuscipes fuscipes ( Gff ). We conducted a genome-wide association (GWA) analysis with field-caught Gff . To increase statistical power, we first improved the Gff genome assembly with whole genome 10X Chromium sequencing, used ddRAD-seq to identify autosomal versus sex-chromosomal regions of the genome with data from 96,965 SNPs, and conducted a GWA with a subset of 50,960 autosomal SNPs from 351 flies. Results assigned a full third of the genome to the sex chromosome, suggested possible sex-chromosome aneuploidy in Gff , and identified a single autosomal SNP to be highly associated with trypanosome infection. The top SNP was ~ 1200 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 indicate that variation upstream of LCAT and/or linked genetic elements are associated with trypanosome infection susceptibility in Gff . This suggests that there may be naturally occurring genetic variation in Gff 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.
Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.
Human African trypanosomiasis (HAT) remains a health threat to sub-Saharan Africa. The current treatments suffer from drug resistance and life-threatening side effects, making drug discovery for HAT still important. A high-throughput screening of the library of pharmaceutically active compounds identified prazosin, an α-adrenoceptor antagonist, that showed selective activity toward Trypanosoma brucei brucei. Furthermore, a series of prazosin analogues were examined, and overall, the new analogues had improved activity and selectivity. To elucidate the binding partner, a biotin-conjugated probe was synthesized, and a protein pulldown assay combined with a proteomic analysis identified the flagellum attachment zone 1 (FAZ1) filament as an interacting partner. Additionally, prazosin treatment resulted in dysfunction of the flagellum of trypanosome cells, which is indicative of a FAZ1 irregularity. We also examined the drug distribution by utilizing immunofluorescence with a designed fluorescent analogue that showed partial colocalization with FAZ1. With the activity of the prazosin analogues, a structure-activity relationship (SAR) was summarized for future lead optimization. Our findings provide a new group of FAZ1 inhibitors as novel antitrypanosomal agents.
Tick-borne diseases including East Coast fever, anaplasmosis and babesiosis constitute a major constraint to improving livestock production worldwide, including Tanzania. Determination of the prevalence and factors associated with the occurrence of pathogens in cattle is important for informed decision making on the control and prevention of these diseases. However, little is known about the epidemiology of these pathogens in cattle in some regions of Tanzania. Therefore, this study aimed at establishing the prevalence of Anaplasma marginale, Babesia bigemina, Babesia bovis and Theileria parva in cattle, determine the risk factors associated with infection with these pathogens and also to assess tick control practices in Gairo and Monduli districts of Tanzania. Out of the 520 cattle sampled, the majority (82.9%) were infested with ticks of different species, predominated by Rhipicephalus decoloratus (42.7%), Amblyomma variegatum (31.3%), Rhipicephalus pulchellus (23.1%) and Rhipicephalus appendiculatus (17.7%). Other ticks that were found on cattle included Rhipicephalus microplus (15.8%), Amblyomma gema (13.8%), Rhipicephalus evertsi (12.9%), Amblyomma lepidum (8.1%), Hyalomma truncatum (2.9%) and Hyalomma albiparmatum (2.1%). On microscopy 23 (4.4%) of 520 cattle were positive for hemoparasites. Of the 23 positive cattle, 13 (2.5%), 6 (1.2%) and 3 (0.6%) were monolithically infected with A. marginale, T. parva, and Bartonella bovis respectively, while one (0.2% %) had co-infections of T. parva and A. marginale. The number of positive cattle increased to 184 (35.4%), when they were subjected to detection with PCR. This included the 23 samples that were positive on microscopy. Based on PCR, the overall prevalence of the pathogens from the two districts was 11.5%, 11.2%, 6.2% and 2.5% for Baconia bigemina, A. marginale, T. parva and B. bovis, respectively. Hemoparasite co-infection occurred in 6.9% of the cattle examined. The prevalence of co-infections was 2.7%, 4%, and 0.02% for T. parva/A. marginale, B. bigemina/A. marginale and B. bigemina/A. marginale/T. parva, respectively. Cattle with co-infections had significantly lower (p < 0.005) mean packed cell volume as compared to cattle with mono-infections. The majority (96%) of cattle examined were subjected to different methods of tick control. A number of risk factors were shown to be associated with the occurrence of tick-borne pathogens in cattle. Higher prevalence of A. marginale may be due to its wide range of biological and mechanical transmission. These findings could be used to strengthen future control programs for ticks and tick-borne diseases in the study areas.
Often conservationists suffer from the ‘shifting base line syndrome’. We illustrate this by elucidating the natural history of Tanzania’s northern Rift Valley over the past centuries. White rhinoceros and possibly the sable antelope went extinct five centuries ago. Two centuries ago Maasai cattle started competing with plains wildlife, but a reset took place through diseases. Wildlife’s zenith was around 1935, before commercial agriculture arose and before people and livestock had recovered from devastating epidemics. Elephant populations recovered from the ivory trade; wildlife benefitted from the expanding range of the tsetse fly. From the 1920s until the 1980s, cattle numbers soared and most fresh water became monopolized by farmers or pastoralists. Unlike in the Serengeti grasslands, the great herbivore migrations that could have developed after the rinderpest eradication were not attained in the grasslands of the northern Rift Valley: in fact, the wildebeest and zebra migrations to a large extent disappeared. It appears that conservationists who have fallen victim to the shifting baseline syndrome are content with the current impoverished natural state. Consequently, with the memory gone and baselines shifted, it is likely that the true natural state of the ecosystem of the northern Rift Valley will not be restored.
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.
Purpose: The boom in Burkina Faso’s artisanal gold mining since 2007 has attracted populations from Côte d'Ivoire and Guinea, which are the West African countries most affected by human African trypanosomiasis (HAT) and therefore increases its risk of re-emergence. Our aim was to update the HAT data in Burkina Faso in the risk of the re-emergence context with the advent of artisanal gold mining.
Methods: The study was carried out in the southwestern Burkina Faso where entomological surveys were conducted using biconical traps in March 2017. Follow by an active medical survey in April 2017, which was targeted the gold panners in 7 villages closer to artisanal gold sites, using CATT, mini-anion exchange centrifugation technique, trypanolysis test (TL) and ELISA test to measure human/tsetse contacts. The buffy coat technique and the TL were also applied in pigs to check their reservoir role of human trypanosomes.
Results: Our results have shown no case of HAT among 958 individuals tested and all the 50 pigs were also negative, but the level of antibodies against tsetse saliva evidenced by ELISA revealed low human/tsetse contact. Moreover, gold panners practise agriculture and breeding in an infected tsetse area, which are increased the risk.
Conclusion: Our results illustrate that the risk of re-emergence is low. The passive surveillance system implemented in 2015 in southwestern Burkina Faso is needed to increase the sentinel sites to better cover this area by taking into account the gold mining. Finally, awareness-raising activities are needed among populations about HAT.
Keywords Human African trypanosomiasis · Risk of re-emergence · Artisanal gold mining · Passive surveillance · Burkina Faso
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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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.
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.
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.
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.
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.