RARE DISEASE
African trypanosomiasis
African trypanosomiasis
African trypanosomiasis
Synonyms: Sleeping sickness
Synonyms: Sleeping sickness
Synonyms: Sleeping sickness
Drug discovery
6
drugs
With orphan designations
Overview
African trypanosomiasis (sleeping sickness) is a vector-borne parasitic disease caused by Trypanosoma brucei gambiense (chronic, West/Central Africa) or T. b. rhodesiense (acute, East/Southern Africa), transmitted via tsetse flies. Early symptoms include fever and lymphadenopathy; late-stage disease involves neuropsychiatric sequelae due to CNS invasion. Diagnosis requires blood/CNS fluid microscopy and serology. Stage- and subspecies-specific treatments include fexinidazole (oral) for early gambiense, nifurtimox-eflornithine combination therapy (NECT) for late-stage gambiense, and suramin/melarsoprol for rhodesiense. WHO reports <1,000 annual cases globally (2023), with elimination targets set for 2030 [2][6][17].
Categories: rare infectious diseases
Research Papers
3,579 drug discovery papers about African trypanosomiasis, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,579 drug discovery papers about African trypanosomiasis, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-25 | Structure-activity relationships of quinoidal derivatives against Trypanosoma brucei.
Quinoidal compounds are a well-established class of redox-active molecules with recognized biological activities, including cytotoxicity and antiparasitic effects. In the context of human African trypanosomiasis (HAT), the demand for novel therapeutic options has encouraged interest in repurposing and further characterizing known compounds. In this study, a set of previously described quinoidal derivatives was evaluated for in vitro activity against Trypanosoma brucei and cytotoxicity against human embryonic kidney (HEK)293 and hepatoblastoma (HepG2) cells. Several compounds exhibited potent antiparasitic activity; however, with the exception of one compound (4), selectivity remained a challenge due to associated cytotoxicity. These findings reinforce the relevance of redox-active scaffolds as privileged structures in the development of trypanocidal agents and highlight the need for further optimization to improve therapeutic windows.
2026-09-24 | Comparative lipidomic profiling of African trypanosomes reveals metabolic distinctions impacting pan-species drug development.
African trypanosomes are a group of pathogens that cause disease in humans (human African trypanosomiasis; HAT) and animals (African animal trypanosomosis; AAT) across sub-Saharan Africa, leading to profound impacts on human health as well as economic instability. Achieving sustainable disease control requires a One Health approach, yet the development of urgently required pan-species chemotherapeutics is severely hindered by a lack of unified biological understanding of the causative species. A major bottleneck in drug discovery is the distinct in vitro requirements of the clinically relevant species. Whilst Trypanosoma brucei is typically cultured in FBS-supplemented culture, T. congolense, the primary cause of AAT, requires the use of goat serum. The differing serum supplementation requirements of these two trypanosome species point to metabolic distinctions, which may be important considerations in developing experimental systems to enable the identification and design of novel, pan-species therapies. In this study, untargeted LC-MS lipidomics analyses were conducted to determine the relative lipidomic profiles of T. brucei and T. congolense bloodstream form parasites. The use of a novel medium formulation that permits effective in vitro culture of both species revealed that their lipidomic profiles are distinct. Notably, ether phospholipids, key molecules in T. brucei lipid biology, are relatively absent in T. congolense. Furthermore, the T. brucei lipidome is enriched with shorter chain saturated lipids, whilst T. congolense exhibits a preference for longer-chain polyunsaturated fatty acids (PUFAs). These observations indicate that there are significant differences in the ways these parasites synthesise and remodel their lipid complement, highlighting an evolutionary divergence between the species that likely carries implications for host-pathogen interactions as well as trypanosome membrane biology. Crucially, defining the species-specific lipid dependencies provides the foundation for pan-species culture systems, thereby removing a critical barrier to the discovery and design of novel therapeutics effective against all African trypanosome species.
2026-09-22 | Ligand-induced reshaping of the conformational free energy landscape drives dynamic restriction in Trypanosoma brucei alternative oxidase.
The alternative oxidase (AOX) of Trypanosoma brucei is a validated therapeutic target for Human African Trypanosomiasis; however, the dynamic mechanisms governing its potent inhibition by lipophilic antibiotics remain poorly resolved. While static crystal structures provide insight into binding poses, the thermodynamic and kinetic drivers of picomolar efficacy are largely undefined. In this study, we employed triplicate microsecond-scale molecular dynamics (MD) simulations coupled with Markov state modeling (MSM) to compare the conformational ensembles of AOX bound to the ubiquinone-2 (UQ2) substrate analogue and the potent inhibitors ascofuranone (ASCO) and ferulenol. Our kinetic analysis reveals that inhibition is governed by a fundamental reshaping of the protein's free energy landscape. The enzyme-substrate (UQ2) complex maintains a dynamic equilibrium across three metastable macrostates (stationary populations of 56.2%, 23.7%, and 20.1%), connected by low energetic barriers that facilitate the rapid conformational cycling required for catalysis. Conversely, inhibitor (ASCO) binding triggers a conformational ensemble, causing the free energy landscape to funnel into a single, deep dynamic restriction containing 98.5% of the population. The stabilization of this trapped state is driven by a core hydrogen-bond network that rigidifies the active site, a process thermodynamically compensated by a substantial increase in entropic disorder at the C-terminus. We propose that high-affinity inhibitors function not solely through steric occlusion, but by inducing a "dynamic restriction" that effectively decouples the enzyme from the thermal fluctuations necessary for catalytic turnover. These findings provide a rigorous kinetic framework for engineering next-generation AOX inhibitors with optimized drug-target residence times.
2026-09-11 | Harnessing Conventional and Nanotechnology-Enabled Combination Therapies to Combat Kinetoplastid Neglected Tropical Diseases.
The kinetoplastid neglected tropical diseases, Chagas disease, African trypanosomiasis, and leishmaniasis, are vector-borne diseases that remain a persistent global health challenge. Progress has been made in combating human African trypanosomiasis, but efforts to contain other kinetoplastid diseases have been slower. The current drugs used for treatment have limitations, such as drug resistance, toxicity, high cost, and limited access. To overcome these challenges, alternative therapeutic strategies are being explored, including drug combinations, drug repurposing, and nanotechnology, which have shown promise in other diseases, like cancer. Combination therapies, both conventional and nanobased, have the potential to enhance antiparasitic efficacy, reduce side effects, and prevent resistance development. This review focuses on the efficacy and safety of drug combinations for kinetoplastid neglected tropical diseases, highlighting current conventional combination therapies and ongoing research on both conventional and nanobased combination therapies in various stages of development. The review aims to provide novel insights and promote future research for the development of innovative, safe, and effective drug combination therapies. This will help in accelerating progress toward the elimination of Kinetoplastid neglected tropical diseases, in line with Sustainable Development Goal 3.3 to ensure healthy lives and promote well-being for all, at every stage of life and to end the epidemics of neglected tropical diseases by 2030.
2026-09-01 | Late-Stage Diversification of Rewired Purine C-Nucleosides Reveals Potent Antitrypanosomatid Agents with In Vivo Efficacy.
Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected, debilitating diseases caused by protozoa of the Trypanosomatidae family. In search of new effective therapies, subtle modifications of purine nucleosides have previously afforded agents that demonstrate promising activity against these protozoa, also in vivo. Here, a library of imidazo[2,1-f][1,2,4]triazine ribosides with varying substituents at C6 (trivial purine numbering) was synthesized through late-stage diversification of a common propyl thioether precursor and screened against a panel of the aforementioned Trypanosomatidae. While numerous analogues displayed selective antitrypanosomatid activity, an N6,N6-butylmethylamine analogue 58 proved exquisitely potent against L. infantum, T. cruzi, and T. bruceispp. This analogue was progressed to an acute Chagas and a bioluminescent visceral leishmaniasis mouse model with encouraging results.
vaccines
2026-07-27 | Beyond antigenic variation: A review of innovative immuno-epidemiologic approaches to trypanosomiasis vaccine design.
Trypanosomiasis remains a major neglected tropical disease, largely uncontrolled due to rising drug resistance and the absence of an effective vaccine. Decades of vaccine failure are primarily linked to the parasite's immune-evasion strategy of Antigenic Variation (AV), driven by continual switching of the Variant Surface Glycoprotein (VSG) coat. This review proposes an integrated immuno-epidemiologic framework that moves beyond VSG-focused strategies by targeting conserved functional vulnerabilities and incorporating population-level transmission dynamics. The approach redirects vaccine development toward invariant, indispensable antigens such as the Transferrin Receptor (TfR), Invariant Surface Glycoproteins (ISGs), and Paraflagellar Rod (PFR) components. Antibodies against these molecules can induce conserved killing mechanisms, including iron starvation or disruption of essential membrane functions - regardless of VSG switching. Advances in reverse vaccinology enable multi-epitope and mRNA platforms to encode these structurally constrained targets, while complementary transmission-blocking and vector-focused strategies aim to interrupt parasite development within tsetse flies. A central argument is that partially protective vaccines (PPVs) can produce substantial epidemiologic benefits by lowering parasitemia, shortening infectious duration, and reducing the probability of vector infection. Such effects can meaningfully suppress transmission without requiring sterilizing immunity. A One Health approach, coupled with realistic population-based efficacy metrics, is essential for future vaccine development. By exploiting conserved molecular constraints and integrating immunologic, ecological, and epidemiologic insights, this framework outlines a practical pathway toward effective trypanosomiasis vaccination.
2025-04-05 | The extracellular region of Trypanosoma congolense Membrane Bound Acid Phosphatase induces partial protection in immunized BALB/c mice.
African trypanosomiasis is a parasitic disease caused by African trypanosomes and there is no vaccine because the trypanosomes possess an intricate machinery for antigenic variation. Owing to the nonsusceptibility of trypanosomes' Membrane-Bound Acid Phosphatase (MBAP; EC 3.1.3.2) to antigenic variation and its central role in molecular trafficking, we hypothesized that MBAP is a promising target for vaccine development. Herein, a DNA vaccine was constructed using recombinant DNA technology to insert the gene of the extracellular portion (EP) of Trypanosoma congolense MBAP without its signal peptide (SP), into a Strep-tag/transin modified mammalian expression vector pVAX1. The construct (EP-SP/pVAX1) was transfected into HepG2 cells. Expression of the antigen (EP-SP) and the subcellular localization were confirmed by Immunofluorescence Assay. Thereafter, two independent vaccination trials with 100 μg EP-SP/pVAX1 were carried out in BALB/c mice. ELISA was used to check immunoglobulin G (IgG) and cytokines (IL-10 and IFN-ɣ) levels. The infection group were experimental infected with 104 T. congolense cells, and the potency of the vaccine was assessed by monitoring parasitemia and survival. There was a significant increase in circulating IgG (P = 0.048), IL-10 (P = 0.031) but no effect on IFN- ɣ (P = 1.001) in the animals. Low parasitaemia characterized by multiple waves with the intermittent clearing of parasites to no detectable levels, and extension of the lifespan by up to 45.45 % was observed with a complete survival of 20 % of vaccinated and infected mice. Together, the results showed that the vaccine construct was partially protective and has tremendous immunogenic potential, suggesting the needs for further studies.
2024-08-02 | Advancement in the development of DNA vaccines against Trypanosoma brucei and future perspective.
Trypanosomes are the extracellular protozoan parasites that cause human African trypanosomiasis disease in humans and nagana disease in animals. Tsetse flies act as a vector for the transmission of the disease in African countries. Animals infected with these parasites become useless or workless, and if not treated, disease can be fatal. There are many side effects associated with old treatments and some of them result in death in 5% of cases. There is a major surface glycoprotein in the parasite known as variant surface glycoprotein. The immune system of the host develops antibodies against this antigen but due to antigenic variation, parasites evade the immune response. Currently, no vaccine is available that provides complete protection. In murine models, only partial protection was observed using certain antigens. In order to develop vaccines against trypanosomes, molecular biology and immunology tools have been used. Immunization is the sole method for the control of disease because the eradication of the vector from endemic areas is an impossible task. Genetic vaccines can carry multiple genes encoding different antigens of the same parasite or different parasites. DNA immunization induces the activation of both cellular immune response and humoral immune response along with the generation of memory. This review highlights the importance of DNA vaccines and advances in the development of DNA vaccines against T. brucei.
2024-03-27 | Advances in the Immunology of the Host-Parasite Interactions in African Trypanosomosis, including Single-Cell Transcriptomics.
Trypanosomes are single-celled extracellular parasites that infect mammals, including humans and livestock, causing global public health concerns and economic losses. These parasites cycle between insect vectors, such as tsetse flies and vertebrate hosts, undergoing morphological, cellular, and biochemical changes. They have remarkable immune evasion mechanisms to escape the host's innate and adaptive immune responses, such as surface coat antigenic variation and the induction of the loss of specificity and memory of antibody responses, enabling the prolongation of infection. Since trypanosomes circulate through the host body in blood and lymph fluid and invade various organs, understanding the interaction between trypanosomes and tissue niches is essential. Here, we present an up-to-date overview of host-parasite interactions and survival strategies for trypanosomes by introducing and discussing the latest studies investigating the transcriptomics of parasites according to life cycle stages, as well as host cells in various tissues and organs, using single-cell and spatial sequencing applications. In recent years, this information has improved our understanding of trypanosomosis by deciphering the diverse populations of parasites in the developmental process, as well as the highly heterogeneous immune and tissue-resident cells involved in anti-trypanosome responses. Ultimately, the goal of these approaches is to gain an in-depth understanding of parasite biology and host immunity, potentially leading to new vaccination and therapeutic strategies against trypanosomosis.
2022-10-06 | Immunoinformatic design of a putative multi-epitope vaccine candidate against Trypanosoma brucei gambiense
Human African trypanosomiasis (HAT) is a neglected tropical disease that is caused by flagellated parasites of the genus Trypanosoma. HAT imposes a significant socio-economic burden on many countries in sub-Saharan Africa and its control is hampered by several drawbacks ranging from the ineffectiveness of drugs, complex dosing regimens, drug resistance, and lack of a vaccine. Despite more than a century of research and investigations, the development of a vaccine to tackle HAT is still challenging due to the complex biology of the pathogens. Advancements in computational modeling coupled with the availability of an unprecedented amount of omics data from different organisms have allowed the design of new generation vaccines that offer better antigenicity and safety profile. One of such new generation approaches is a multi-epitope vaccine (MEV) designed from a collection of antigenic peptides. A MEV can stimulate both cellular and humoral immune responses as well as avoiding possible allergenic reactions. Herein, we take advantage of this approach to design a MEV from conserved hypothetical plasma membrane proteins of Trypanosoma brucei gambiense, the trypanosome subspecies that is responsible for the west and central African forms of HAT. The designed MEV is 402 amino acids long (41.5 kDa). It is predicted to be antigenic, non-toxic, to assume a stable 3D conformation, and to interact with a key immune receptor. In addition, immune simulation foresaw adequate immune stimulation by the putative antigen and a lasting memory. Therefore, the designed chimeric vaccine represents a potential candidate that could be used to target HAT.
proteins
2026-06-01 | The bromodomain protein Bdf3 is sufficient to activate expression of a procyclin gene in bloodstream stage African trypanosomes.
The early-branching eukaryotic parasite, Trypanosoma brucei, lives extracellularly in the mammalian host, where it expresses variant surface glycoprotein (VSG). Antigenic variation of VSGs allows the parasite to evade the host immune response while in the bloodstream. Upon transition to the tsetse fly vector, the parasite remodels its surface to express procyclin protein from a limited set of EP and GPEET genes. While the environmental signals that trigger the switch from expressing VSG genes to expressing EP and GPEET genes are known, the molecular mechanism that initiates transcription of the EP and GPEET genes during parasite differentiation to the procyclic stage within the tsetse is not well understood. Previous work has shown that the chromatin-interacting bromodomain protein Bdf3 is absent from the RNA polymerase I promoter of the EP locus in bloodstream parasites, but appears there shortly after initiation of differentiation from the bloodstream to the procyclic stage. Here, we show that tethering of Bdf3 to the EP promoter using a dCas9-Bdf3 fusion protein and a guide RNA is sufficient to increase transcript levels of EP1 in bloodstream parasites, where the gene is normally silenced. This result supports the model that Bdf3 appears at the EP locus during differentiation to facilitate initiation of transcription, which is consistent with the role of Bdf3 as a transcriptional activator in other systems. Understanding gene regulatory mechanisms in this early-branching eukaryote may help build a more complete picture of the conserved and unique features of gene regulatory proteins across diverse biological systems. The Trypanosoma brucei parasite is transmitted via the tsetse fly vector to a mammalian host , where it causes African trypanosomiasis, a fatal disease that imposes a severe human and economic burden for people living in areas of sub-Saharan Africa. While drug treatments have improved for some strains, some infections still require treatment with drugs that have serious side effects. One avenue for drug development is to try to manipulate the life cycle of the parasite to make it poorly adapted to the mammalian host. However, this requires detailed knowledge of the mechanisms by which parasites regulate their genes as they progress through the life cycle. Here, we show that the DNA-interacting bromodomain protein Bdf3 may be a key driver for turning on insect-specific genes that code for insect-stage surface proteins. This finding could aid in the development of life cycle-manipulating drugs and shed light on how gene regulatory mechanisms evolved.
2025-12-31 | IL-10 Plays a Critical Role in Mitigating Acute Anaemia Development During African Trypanosome Infection.
During the first week of T. b. brucei infection, pro-inflammatory IFN-γ production drives acute anaemia by promoting red blood cell clearance by activated macrophages in concert with insufficient bone marrow compensation. The latter is followed by a partial recovery phase, which later progresses to chronic anaemia. To compensate for acute anaemia, stress-induced extramedullary erythropoiesis occurs in the spleen. However, the role of IL-10, a key anti-inflammatory cytokine in regulating stress-induced acute anaemia during African trypanosomosis (AT), remains unclear. Using both genetic and pharmacological approaches, we show that IL-10 is essential to limit acute anaemia by dampening inflammation and promoting splenic erythropoiesis, enabling recovery. More specifically, IL-10 blockade impairs erythropoiesis in both bone marrow and spleen, particularly at early erythroid differentiation stages, and associates with reduced central macrophage (CM) numbers in the bone marrow. In contrast, the co-inhibition of IL-10 and IFN-γ reduces inflammation and partially restores splenic CM numbers and erythropoiesis, highlighting IFN-γ's suppressive role in erythropoiesis. Overall, these findings underscore IL-10's key role in regulating stress-induced erythropoiesis during AT by modulating erythroid differentiation and CM abundance, thereby limiting immune-mediated acute anaemia. Consequently, timely adjustment of the IL-10/IFN-γ balance may enhance erythropoiesis and offer a potential therapeutic strategy to mitigate anaemia development.
2025-09-15 | Genome-wide overexpression screen reveals a novel transcription termination factor in Trypanosoma brucei.
Trypanosoma brucei is a protozoan parasite that causes African trypanosomiasis. We performed an overexpression library screen to gain insights into essential cellular processes in T. brucei and identified genes whose overexpression impaired parasite growth. One of the three top-ranking candidates we validated exhibited a notable phenotype. Tb FOP, an uncharacterized protein, has an N-terminal arginine-rich domain and a C-terminal FOP (Friend Of PRMT1) domain. Tb FOP overexpression substantially increases antisense transcription across the genome, particularly at Transcription Termination Sites (TTSs). This phenotype resembles that observed in trypanosome cells lacking a component of the transcription termination complex PJW/PP1 and cells lacking TTS chromatin marks, two histone variants, and base J DNA modification. Base J is synthesized in two steps: hydroxylation of dT to 5-hydroxymethyl-dU (5hmU) by JBP1 & JBP2, and the glucosylation of 5hmU to glucosyl-5hmU (base J) by JGT. Interestingly, human FOP interacts with 5-hydroxymethyl-dC (5hmC) generated by TET enzymes that are orthologs of T. brucei JBP1/2. Our study reveals Tb FOP as a novel transcription termination factor that may interact with TTS-associated 5hmU, thereby interfering with the function of termination factors. We propose that Tb FOP overexpression disrupts termination, leading to widespread transcription defects and trypanosome cell death.
2024-10-25 | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease.
Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.
2024-10-24 | Spiroplasma endosymbiont reduction of host lipid synthesis and Stomoxyn-like peptide contribute to trypanosome resistance in the tsetse fly Glossina fuscipes
Abstract Tsetse flies ( Glossina spp.) vector African trypanosomes that cause devastating diseases in humans and domestic animals. Within the Glossina genus, species in the Palpalis subgroup exhibit greater resistance to trypanosome infections compared to those in the Morsitans subgroup. Varying microbiota composition and species-specific genetic traits can significantly influence the efficiency of parasite transmission. Notably, infections with the endosymbiotic bacterium Spiroplasma have been documented in several Palpalis subgroup species, including Glossina fuscipes fuscipes ( Gff ). While Spiroplasma infections in Gff are known to hinder trypanosome transmission, the underlying mechanisms remain unknown. To investigate Spiroplasma- mediated factors affecting Gff vector competence, we conducted high-throughput RNA sequencing of the midgut tissue along with functional assays. Our findings reveal elevated oxidative stress in the midgut environment in the presence of Spiroplasma , evidenced by increased expression of nitric oxide synthase, which catalyzes the production of trypanocidal nitric oxide. Additionally, we observed impaired lipid biosynthesis leading to a reduction of this important class of nutrients essential for parasite and host physiologies. In contrast, trypanosome infections in Gff’s midgut significantly upregulated various immunity-related genes, including a small peptide, Stomoxyn-like , homologous to Stomoxyns first discovered in the stable fly Stomoxys calcitrans . We observed that the Stomoxyn-like locus is exclusive to the genomes of Palpalis subgroup tsetse species. Gff Stomoxyn is constitutively expressed in the cardia (proventriculus) and synthetic Gff Stomoxyn exhibits potent activity against Escherichia coli and bloodstream form of Trypanosoma brucei parasites, while showing no effect against insect stage procyclic forms or tsetse’s commensal endosymbiont Sodalis in vitro . Reducing Gff Stomoxyn levels significantly increased trypanosome infection prevalence, indicating its potential trypanocidal role in vivo . Collectively, our results suggest that the enhanced resistance to trypanosomes observed in Spiroplasma -infected Gff may be due to the reduced lipid availability necessary for parasite metabolic maintenance. Furthermore, Gff Stomoxyn could play a crucial role in the initial immune response(s) against mammalian parasites early in the infection process in the midgut and prevent gut colonization. We discuss the molecular characteristics of Gff Stomoxyn, its spatial and temporal expression regulation and its microbicidal activity against Trypanosome parasites. Our findings reinforce the nutritional influences of microbiota on host physiology and host-pathogen dynamics. Author Summary The tsetse fly, Glossina fuscipes fuscipes ( Gff ) is of high public health relevance. Gff exhibits strong innate resistance to trypanosomes, especially when infected with the endosymbiotic bacterium Spiroplasma . This study investigated how the bacterium Spiroplasma inside Gff enables them to be resistant to trypanosome infection. Our results indicate alterations in host lipid metabolism with reduction in levels of triglycerides, suggesting a potential metabolic barrier that limits the viability to parasite. In addition, we discovered a small peptide, stomoxyn, exclusively in Gff and related Palpalis tsetse species. We have shown that Gff synthetic Stomoxyn has antibacterial and antitrypanosomal properties and lowering Stomoxyn levels in Gff correlates with increased parasite prevalence. We suggest that strategies to increase Spiroplasma prevalence or enhance stomoxyn expression through paratransgenic approaches could be promising avenues for reducing trypanosomiasis transmission.
oligonucleotides
2026-09-07 | Immunoinformatics Approach for the Designing of a Novel mRNA Vaccine Candidate Against Trypanosoma brucei.
Trypanosoma brucei causes Human African Trypanosomiasis (HAT), which has a devastating impact on an individual's health. Currently, there is no FDA-approved vaccine for HAT prevention. Therefore, reverse vaccinology approaches were utilized to design an mRNA vaccine candidate. Variant surface glycoprotein, heat shock protein 70, and vacuolar transporter chaperone complex of T. brucei were targeted to predict immunogenic, non-allergenic, and non-toxic peptides. The vaccine candidate was evaluated for population coverage, biophysical attributes, structural stability, and refinement. Molecular docking, MD simulation, and MM-GBSA analyses evaluate receptor binding and complex stability. Codon optimization and in-silico cloning were conducted in Escherichia coli (strain K12) using pET-28a( +). Immune simulations predicted humoral and cellular responses, while mRNA integrity was evaluated through MFE analysis. The vaccine candidate achieved 100% global population coverage. Biophysical attributes indicated aliphaticity 71.23, and GRAVY score -0.719. Predicted tertiary structure (TM-score 0.65 ± 0.13, and C-score -0.50) was refined with stable validation metrics (Ramachandran score 86.8%, and Z-score -5.26). Docking predicted significant binding with TLR-2 and TLR-4 (energy scores -1013.5 and -1002.8 kJ/mol), validated through MD simulation, PCA, DCCM, MM-GBSA analyses. Codon optimization (CAI 0.9688; GC 44.70%) indicated high expression potential, and immune simulation exhibits robust antibody and cell-mediated responses, including elevated B lymphocyte, T lymphocyte levels, and IgM, IgG titers. Finally, the structural integrity of mRNA was predicted by MFE values. This in-silico designed vaccine demonstrated strong structural stability, receptor interactions, and immunogenic potential against T. brucei. Experimental validation and in-vivo studies are required to verify safety and efficacy of vaccine candidate.
2026-05-24 | Aptamers as immunomodulatory therapeutic alternatives targeting neglected tropical diseases (NTDs).
Neglected tropical diseases (NTDs) comprise a heterogeneous group of infections that disproportionately affect populations in low- and middle-income countries, where limited access to diagnostics, therapeutics, and surveillance perpetuates disease burden. Conventional strategies based on antibodies and small-molecule drugs face major challenges, including high production costs, limited stability, cross-reactivity, toxicity, and the emergence of drug resistance. In this context, aptamers, short single-stranded nucleic acids selected by SELEX, have emerged as versatile immunomodulatory tools with significant potential for the diagnosis and treatment of NTDs. This chapter provides a comprehensive overview of aptamer-based strategies targeting major NTDs, with particular emphasis on human African trypanosomiasis and arboviral infections such as dengue, Zika, and chikungunya. Aptamers directed against conserved parasite and viral epitopes demonstrate the capacity to circumvent immune evasion mechanisms, including antigenic variation and serotype diversity, while enabling highly specific recognition and internalization. In African trypanosomes, RNA aptamers targeting variant surface glycoproteins exploit the flagellar pocket for targeted drug delivery, offering a novel approach to overcome therapeutic resistance. In arboviral diseases, aptamers have been successfully integrated into advanced diagnostic platforms, including competitive ELISA, electrochemical, and capacitive biosensors, achieving high sensitivity, rapid response times, and minimal cross-reactivity among closely related flaviviruses. Beyond diagnostics, selected aptamers exhibit neutralizing activity and immunomodulatory effects by interfering with host-pathogen interactions and innate immune signaling pathways.
2025-10-09 | DNA Vaccine Encoding Trypanosoma brucei MSP-B Elicited IgG and IFN-γ Responses and Partial Protection in Immunised Mice.
As an effort towards vaccine development against African trypanosomiasis, we studied key parasite molecules that mediate VSG functions, specifically the major surface protease-B of Trypanosoma brucei that catalyses proteolytic removal of old VSGs for expression of new ones, an important stage-specific function that allows the parasite to survive in its host, thus making it an attractive candidate for vaccine development. Herein, the Tbmsp-b gene was cloned into a pVAX-1 plasmid to produce the pVAX-1-Tbmsp-b construct for DNA vaccine trials. BALB/c mice were immunised by intradermal injection with a 100 μg dose of the construct thrice on Days 0, 21 and 42, then inoculated with 2000 parasites on Day 56. Anti-trypanosome-specific antibody (IgG) and cytokine (IFN-γ) were monitored by ELISA from sera of immunised and unimmunised mice. Immunised mice showed significantly (p < 0.05) higher IgG and IFN-γ responses, lower parasitaemia (by 75% and 51.2% of parasitaemic scores on the first and fifth week of infection) and longevity by up to 22 days compared to unimmunised mice. These results showed that the construct provided partial protection to virulent T. b. brucei (Federe strain) infection in susceptible BALB/c mice, suggesting the potential for using MSP-B as an antigen in DNA vaccine development against African trypanosomiasis.
2025-07-15 | Current Status and Prospects for Development of a Vaccine against African Trypanosoma: A Review
Background: African trypanosomiasis, a disease caused by Trypanosoma brucei, remains a significant health challenge in sub-Saharan Africa, particularly in rural communities with limited healthcare access. Despite control efforts, the disease persists due to the parasite's complex immune evasion mechanisms, including antigenic variation and destruction of the host's humoral immune response. Current treatments face limitations, and the development of an effective vaccine is stalled by the parasite's genetic diversity and insufficient research funding. Objective: This review aimed to compile recent advancements in vaccine development against African trypanosomiasis, evaluate potential vaccine candidates, and identify challenges and future directions for developing an effective vaccine. Method: We adopted the PRISMA protocol to guide our systematic literature on Medline/PubMed and Google Scholar databases, focusing on studies published between 2005 and April 2025. Results: The findings revealed several encouraging approaches to vaccine development against African trypanosomiasis. DNA vaccines targeting specific parasite proteins have demonstrated partial protection in animal studies, stimulating immune responses that delay disease progression. The T. brucei membrane surface protein B (Tbmsp-b) gene was cloned into a pVAX-1 plasmid and administered into a BALB/c mice model, conferring partial protection. Similarly, DNA plasmid encoding an invariant surface glycoprotein (ISG) of T. brucei provided partial protection against T. brucei in the BALB/c mice model. Plasmid DNA containing the 5′-terminal region of the T. brucei brucei trans-sialidase (nTSA) gene also provided partial protection in BALB/c mice. Innovative computer-designed vaccines, which combine multiple T. brucei epitopes, showed particular promise against the parasite's variability in terms of antigenicity.
2022-08-15 | Oligo targeting for profiling drug resistance mutations in the parasitic trypanosomatids.
Trypanosomatids cause the neglected tropical diseases, sleeping sickness, Chagas disease and the leishmaniases. Studies on these lethal parasites would be further facilitated by new and improved genetic technologies. Scalable precision editing methods, for example, could be used to improve our understanding of potential mutations associated with drug resistance, a current priority given that several new anti-trypanosomal drugs, with known targets, are currently in clinical development. We report the development of a simple oligo targeting method for rapid and precise editing of priority drug targets in otherwise wild type trypanosomatids. In Trypanosoma brucei, approx. 50-b single-stranded oligodeoxynucleotides were optimal, multiple base edits could be incorporated, and editing efficiency was substantially increased when mismatch repair was suppressed. Resistance-associated edits were introduced in T. brucei cyclin dependent kinase 12 (CRK12, L482F) or cleavage and polyadenylation specificity factor 3 (N232H), in the Trypanosoma cruzi proteasome β5 subunit (G208S), or in Leishmania donovani CRK12 (G572D). We further implemented oligo targeting for site saturation mutagenesis, targeting codon G492 in T. brucei CRK12. This approach, combined with amplicon sequencing for codon variant scoring, revealed fourteen resistance conferring G492 edits encoding six distinct amino acids. The outputs confirm on-target drug activity, reveal a variety of resistance-associated mutations, and facilitate rapid assessment of potential impacts on drug efficacy.
other
2026-09-10 | Friends or foes: Unraveling the tsetse fly-Spiroplasma symbiosis.
Tsetse flies (Glossina spp.) transmit African trypanosomes, the causative agents of human African and African animal trypanosomiases (HAT and AAT, respectively). These neglected tropical diseases impose significant public health and economic burdens across sub-Saharan Africa. Trypanosome transmission by tsetse flies is influenced by multiple factors, including host genetic background, ecological factors, and interactions with heritable microbial endosymbionts. Spiroplasma glossinidia has recently emerged as an important modulator of tsetse reproductive fitness and vector competence, making it a potential target for symbiont-based vector control strategies. In this review, we summarize the current knowledge of the tsetse-Spiroplasma symbiosis. We detail Spiroplasma's spatial and temporal infection dynamics in laboratory-reared and natural populations. Additionally, we highlight key aspects of the bacterium's genomics, phylogenetics, and physiological interactions with its tsetse host, including influences on host gene expression reproductive physiology, and vector competence. Finally, we discuss how the tsetse-Spiroplasma symbiosis could be harnessed to develop innovative, biological-based vector control and trypanosome transmission-blocking strategies, and we identify critical gaps that must be addressed to translate these findings into effective disease control interventions.
2026-03-27 | Germline-targeted baboon apolipoprotein L-1 protects mice against African trypanosomes.
Some primates are immune to infection by most African trypanosome parasites due to apolipoprotein L-1 (APOL1), a primate-specific ion channel-forming protein. Our long-term objective has been to reduce African trypanosomiasis in livestock by genetic bioengineering of cattle with primate APOL1. To select which primate APOL1, we analyzed Papio ssp. APOL1 proteins and found that Papio hamadryas APOL1 was a strong candidate for transgenic animal production based on its trypanosome-killing capacity, ion channel properties, and stability. We generated seven transgenic murine lines based on the P. hamadryas APOL1 sequence and used these mice to investigate the level of APOL1 expression required for trypanosome immunity in vivo. We challenged the murine lines with three human and four livestock trypanosome isolates. P. hamadryas APOL1 provided protection against all of the human and three of the livestock trypanosome isolates, though not against Trypanosoma vivax despite the logical hypothesis that APOL1 plays a role in primate immunity to that parasite. Occasionally, lower APOL1 expression in heterozygote mice selected for the emergence of APOL1 resistant parasites in several trypanosome spp. Alarmingly, these resistant parasites were also resistant to high levels of APOL1 in homozygous mice, indicating an increase in virulence. A more-highly expressed chimeric APOL1 transgene encoding Homo sapiens APOL1 with the P. hamadryas APOL1 C-terminus was more effectively protective in heterozygote mice; however, we could not produce homozygous mice, suggesting endogenous toxicity to the mice. Together, these data bear relevance to our long-term objective to generate transgenic APOL1 cattle, the feasibility of which is discussed.
2026-03-16 | Dual faces of γδ T cells in trypanosomatid infections.
In this review, we tell the story of how two related parasites that belong to the same genus, Trypanosoma brucei and Trypanosoma cruzi, cause very distinct lethal diseases and how γδ T cells help shape these outcomes. It synthesizes current knowledge on γδ T-cell responses to T. brucei and T. cruzi, highlighting shared and parasite-specific features. Here we emphasize how γδ T-cell cytotoxic versus regulatory programs and tissue residency in blood, lymphoid organs, liver, gut, heart, and skin influence early parasite control, chronic persistence, and immunopathology. Finally, we discuss the gaps that need to be filled and how these insights may inform new interventions, including modulation of γδ function, γδ-targeted vaccine strategies, and γδ-based biomarkers for host-directed therapies in Chagas disease and human African trypanosomiasis.
2025-10-20 | Cure of experimental Trypanosoma vivax infection with a single dose of an unmodified antibody-based drug targeting the invariant flagellum cell surface protein IFX.
Animal African trypanosomiasis (AAT) is an infectious wasting disease of economically important livestock caused by Trypanosoma spp. parasites. The disease is primarily caused by two species: Trypanosoma congolense and Trypanosoma vivax, which are endemic in many African countries. AAT is managed by therapeutic and prophylactic drugs; however, resistance is now widely reported, and the development of new drugs has been impeded due to a chronic lack of investment. Recently, we identified an invariant flagellar-associated cell surface protein (IFX) that could elicit protective immune responses when used as a vaccine against T. vivax. We showed that a complement-recruiting anti-IFX monoclonal antibody can prevent infection when used prophylactically. Here, we show that this same unmodified antibody can be used to cure T. vivax infections in a murine experimental model. Importantly, we show that infections can be treated with a single dose and demonstrate full cure by the lack of detectable parasites in peripheral tissues even after immunosuppression. Using structural modeling and site-directed mutagenesis, we localize the protective antibody epitope, thereby identifying targetable regions on IFX to improve vaccine design. Together, these findings validate IFX as both a prophylactic and curative drug target that could be useful in the management of AAT.IMPORTANCETrypanosoma vivax is a parasite that causes animal African trypanosomiasis (AAT), a chronic wasting disease that infects economically important livestock animals, which is a particular problem in African countries south of the Sahara. The impact of this disease is significant: it is responsible for over 3 million cattle deaths and an estimated $4.5 billion of annual lost productivity. There is a desperate need to develop new control measures because resistance is now widely reported to the drugs commonly used to treat this infection. We show here that a single dose of an unmodified monoclonal antibody that recognizes IFX-a parasite cell surface protein localized to the flagellum-is sufficient to cure an established T. vivax infection with no parasite reservoirs detectable in peripheral tissues. Our finding validates IFX as a new drug target and provides a rationale route to the development of new drugs to target AAT.
2025-09-10 | Molecular Detection and Phylogenetic Characterization of Wolbachia Strains in Glossina Species from Nigerian Conservation Areas
Tsetse flies (Glossina spp.), the vectors of human and animal African trypanosomiasis, continue to exert a profound toll on public health and livestock productivity in Nigeria. This study investigates the prevalence, seasonal dynamics, and genetic diversity of Wolbachia endosymbionts in 7,632 wild-caught tsetse flies sampled from four ecologically distinct conservation sites: Yankari Game Reserve, Kainji Lake National Park, Kagarko Forest, and Ijah Gwari Forest. Molecular screening based on wsp gene sequencing detected Wolbachia in 1,771 flies, with infection rates rising significantly during the wet season (e.g., G. morsitans submorsitans: 75.4% vs. 39.8% in dry season; p < 0.001). Female flies showed consistently higher infection prevalence, reinforcing the role of vertical transmission. Phylogenetic reconstruction revealed nine Wolbachia strains spanning supergroups A and B, including a putatively unique regional variant (wsp9) restricted to northern Nigeria. Bacterial load exhibited a strong age-dependent pattern (r = 0.912, p < 0.001), and elevated GC content (~ 63%) suggested possible adaptation to savanna thermal conditions. These findings highlight the ecological flexibility of Wolbachia within natural tsetse populations and point to its potential application in vector control—particularly through mechanisms like cytoplasmic incompatibility. By combining molecular detection, ecological data, and evolutionary analysis, this study lays the groundwork for tailored, climate-sensitive Wolbachia-based strategies to reduce tsetse populations and support trypanosomiasis control in Nigeria.
small molecules
2026-09-25 | Structure-activity relationships of quinoidal derivatives against Trypanosoma brucei.
Quinoidal compounds are a well-established class of redox-active molecules with recognized biological activities, including cytotoxicity and antiparasitic effects. In the context of human African trypanosomiasis (HAT), the demand for novel therapeutic options has encouraged interest in repurposing and further characterizing known compounds. In this study, a set of previously described quinoidal derivatives was evaluated for in vitro activity against Trypanosoma brucei and cytotoxicity against human embryonic kidney (HEK)293 and hepatoblastoma (HepG2) cells. Several compounds exhibited potent antiparasitic activity; however, with the exception of one compound (4), selectivity remained a challenge due to associated cytotoxicity. These findings reinforce the relevance of redox-active scaffolds as privileged structures in the development of trypanocidal agents and highlight the need for further optimization to improve therapeutic windows.
2026-09-24 | Comparative lipidomic profiling of African trypanosomes reveals metabolic distinctions impacting pan-species drug development.
African trypanosomes are a group of pathogens that cause disease in humans (human African trypanosomiasis; HAT) and animals (African animal trypanosomosis; AAT) across sub-Saharan Africa, leading to profound impacts on human health as well as economic instability. Achieving sustainable disease control requires a One Health approach, yet the development of urgently required pan-species chemotherapeutics is severely hindered by a lack of unified biological understanding of the causative species. A major bottleneck in drug discovery is the distinct in vitro requirements of the clinically relevant species. Whilst Trypanosoma brucei is typically cultured in FBS-supplemented culture, T. congolense, the primary cause of AAT, requires the use of goat serum. The differing serum supplementation requirements of these two trypanosome species point to metabolic distinctions, which may be important considerations in developing experimental systems to enable the identification and design of novel, pan-species therapies. In this study, untargeted LC-MS lipidomics analyses were conducted to determine the relative lipidomic profiles of T. brucei and T. congolense bloodstream form parasites. The use of a novel medium formulation that permits effective in vitro culture of both species revealed that their lipidomic profiles are distinct. Notably, ether phospholipids, key molecules in T. brucei lipid biology, are relatively absent in T. congolense. Furthermore, the T. brucei lipidome is enriched with shorter chain saturated lipids, whilst T. congolense exhibits a preference for longer-chain polyunsaturated fatty acids (PUFAs). These observations indicate that there are significant differences in the ways these parasites synthesise and remodel their lipid complement, highlighting an evolutionary divergence between the species that likely carries implications for host-pathogen interactions as well as trypanosome membrane biology. Crucially, defining the species-specific lipid dependencies provides the foundation for pan-species culture systems, thereby removing a critical barrier to the discovery and design of novel therapeutics effective against all African trypanosome species.
2026-09-22 | Ligand-induced reshaping of the conformational free energy landscape drives dynamic restriction in Trypanosoma brucei alternative oxidase.
The alternative oxidase (AOX) of Trypanosoma brucei is a validated therapeutic target for Human African Trypanosomiasis; however, the dynamic mechanisms governing its potent inhibition by lipophilic antibiotics remain poorly resolved. While static crystal structures provide insight into binding poses, the thermodynamic and kinetic drivers of picomolar efficacy are largely undefined. In this study, we employed triplicate microsecond-scale molecular dynamics (MD) simulations coupled with Markov state modeling (MSM) to compare the conformational ensembles of AOX bound to the ubiquinone-2 (UQ2) substrate analogue and the potent inhibitors ascofuranone (ASCO) and ferulenol. Our kinetic analysis reveals that inhibition is governed by a fundamental reshaping of the protein's free energy landscape. The enzyme-substrate (UQ2) complex maintains a dynamic equilibrium across three metastable macrostates (stationary populations of 56.2%, 23.7%, and 20.1%), connected by low energetic barriers that facilitate the rapid conformational cycling required for catalysis. Conversely, inhibitor (ASCO) binding triggers a conformational ensemble, causing the free energy landscape to funnel into a single, deep dynamic restriction containing 98.5% of the population. The stabilization of this trapped state is driven by a core hydrogen-bond network that rigidifies the active site, a process thermodynamically compensated by a substantial increase in entropic disorder at the C-terminus. We propose that high-affinity inhibitors function not solely through steric occlusion, but by inducing a "dynamic restriction" that effectively decouples the enzyme from the thermal fluctuations necessary for catalytic turnover. These findings provide a rigorous kinetic framework for engineering next-generation AOX inhibitors with optimized drug-target residence times.
2026-09-11 | Harnessing Conventional and Nanotechnology-Enabled Combination Therapies to Combat Kinetoplastid Neglected Tropical Diseases.
The kinetoplastid neglected tropical diseases, Chagas disease, African trypanosomiasis, and leishmaniasis, are vector-borne diseases that remain a persistent global health challenge. Progress has been made in combating human African trypanosomiasis, but efforts to contain other kinetoplastid diseases have been slower. The current drugs used for treatment have limitations, such as drug resistance, toxicity, high cost, and limited access. To overcome these challenges, alternative therapeutic strategies are being explored, including drug combinations, drug repurposing, and nanotechnology, which have shown promise in other diseases, like cancer. Combination therapies, both conventional and nanobased, have the potential to enhance antiparasitic efficacy, reduce side effects, and prevent resistance development. This review focuses on the efficacy and safety of drug combinations for kinetoplastid neglected tropical diseases, highlighting current conventional combination therapies and ongoing research on both conventional and nanobased combination therapies in various stages of development. The review aims to provide novel insights and promote future research for the development of innovative, safe, and effective drug combination therapies. This will help in accelerating progress toward the elimination of Kinetoplastid neglected tropical diseases, in line with Sustainable Development Goal 3.3 to ensure healthy lives and promote well-being for all, at every stage of life and to end the epidemics of neglected tropical diseases by 2030.
2026-09-01 | Late-Stage Diversification of Rewired Purine C-Nucleosides Reveals Potent Antitrypanosomatid Agents with In Vivo Efficacy.
Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected, debilitating diseases caused by protozoa of the Trypanosomatidae family. In search of new effective therapies, subtle modifications of purine nucleosides have previously afforded agents that demonstrate promising activity against these protozoa, also in vivo. Here, a library of imidazo[2,1-f][1,2,4]triazine ribosides with varying substituents at C6 (trivial purine numbering) was synthesized through late-stage diversification of a common propyl thioether precursor and screened against a panel of the aforementioned Trypanosomatidae. While numerous analogues displayed selective antitrypanosomatid activity, an N6,N6-butylmethylamine analogue 58 proved exquisitely potent against L. infantum, T. cruzi, and T. bruceispp. This analogue was progressed to an acute Chagas and a bioluminescent visceral leishmaniasis mouse model with encouraging results.
vaccines
2026-07-27 | Beyond antigenic variation: A review of innovative immuno-epidemiologic approaches to trypanosomiasis vaccine design.
Trypanosomiasis remains a major neglected tropical disease, largely uncontrolled due to rising drug resistance and the absence of an effective vaccine. Decades of vaccine failure are primarily linked to the parasite's immune-evasion strategy of Antigenic Variation (AV), driven by continual switching of the Variant Surface Glycoprotein (VSG) coat. This review proposes an integrated immuno-epidemiologic framework that moves beyond VSG-focused strategies by targeting conserved functional vulnerabilities and incorporating population-level transmission dynamics. The approach redirects vaccine development toward invariant, indispensable antigens such as the Transferrin Receptor (TfR), Invariant Surface Glycoproteins (ISGs), and Paraflagellar Rod (PFR) components. Antibodies against these molecules can induce conserved killing mechanisms, including iron starvation or disruption of essential membrane functions - regardless of VSG switching. Advances in reverse vaccinology enable multi-epitope and mRNA platforms to encode these structurally constrained targets, while complementary transmission-blocking and vector-focused strategies aim to interrupt parasite development within tsetse flies. A central argument is that partially protective vaccines (PPVs) can produce substantial epidemiologic benefits by lowering parasitemia, shortening infectious duration, and reducing the probability of vector infection. Such effects can meaningfully suppress transmission without requiring sterilizing immunity. A One Health approach, coupled with realistic population-based efficacy metrics, is essential for future vaccine development. By exploiting conserved molecular constraints and integrating immunologic, ecological, and epidemiologic insights, this framework outlines a practical pathway toward effective trypanosomiasis vaccination.
2025-04-05 | The extracellular region of Trypanosoma congolense Membrane Bound Acid Phosphatase induces partial protection in immunized BALB/c mice.
African trypanosomiasis is a parasitic disease caused by African trypanosomes and there is no vaccine because the trypanosomes possess an intricate machinery for antigenic variation. Owing to the nonsusceptibility of trypanosomes' Membrane-Bound Acid Phosphatase (MBAP; EC 3.1.3.2) to antigenic variation and its central role in molecular trafficking, we hypothesized that MBAP is a promising target for vaccine development. Herein, a DNA vaccine was constructed using recombinant DNA technology to insert the gene of the extracellular portion (EP) of Trypanosoma congolense MBAP without its signal peptide (SP), into a Strep-tag/transin modified mammalian expression vector pVAX1. The construct (EP-SP/pVAX1) was transfected into HepG2 cells. Expression of the antigen (EP-SP) and the subcellular localization were confirmed by Immunofluorescence Assay. Thereafter, two independent vaccination trials with 100 μg EP-SP/pVAX1 were carried out in BALB/c mice. ELISA was used to check immunoglobulin G (IgG) and cytokines (IL-10 and IFN-ɣ) levels. The infection group were experimental infected with 104 T. congolense cells, and the potency of the vaccine was assessed by monitoring parasitemia and survival. There was a significant increase in circulating IgG (P = 0.048), IL-10 (P = 0.031) but no effect on IFN- ɣ (P = 1.001) in the animals. Low parasitaemia characterized by multiple waves with the intermittent clearing of parasites to no detectable levels, and extension of the lifespan by up to 45.45 % was observed with a complete survival of 20 % of vaccinated and infected mice. Together, the results showed that the vaccine construct was partially protective and has tremendous immunogenic potential, suggesting the needs for further studies.
2024-08-02 | Advancement in the development of DNA vaccines against Trypanosoma brucei and future perspective.
Trypanosomes are the extracellular protozoan parasites that cause human African trypanosomiasis disease in humans and nagana disease in animals. Tsetse flies act as a vector for the transmission of the disease in African countries. Animals infected with these parasites become useless or workless, and if not treated, disease can be fatal. There are many side effects associated with old treatments and some of them result in death in 5% of cases. There is a major surface glycoprotein in the parasite known as variant surface glycoprotein. The immune system of the host develops antibodies against this antigen but due to antigenic variation, parasites evade the immune response. Currently, no vaccine is available that provides complete protection. In murine models, only partial protection was observed using certain antigens. In order to develop vaccines against trypanosomes, molecular biology and immunology tools have been used. Immunization is the sole method for the control of disease because the eradication of the vector from endemic areas is an impossible task. Genetic vaccines can carry multiple genes encoding different antigens of the same parasite or different parasites. DNA immunization induces the activation of both cellular immune response and humoral immune response along with the generation of memory. This review highlights the importance of DNA vaccines and advances in the development of DNA vaccines against T. brucei.
2024-03-27 | Advances in the Immunology of the Host-Parasite Interactions in African Trypanosomosis, including Single-Cell Transcriptomics.
Trypanosomes are single-celled extracellular parasites that infect mammals, including humans and livestock, causing global public health concerns and economic losses. These parasites cycle between insect vectors, such as tsetse flies and vertebrate hosts, undergoing morphological, cellular, and biochemical changes. They have remarkable immune evasion mechanisms to escape the host's innate and adaptive immune responses, such as surface coat antigenic variation and the induction of the loss of specificity and memory of antibody responses, enabling the prolongation of infection. Since trypanosomes circulate through the host body in blood and lymph fluid and invade various organs, understanding the interaction between trypanosomes and tissue niches is essential. Here, we present an up-to-date overview of host-parasite interactions and survival strategies for trypanosomes by introducing and discussing the latest studies investigating the transcriptomics of parasites according to life cycle stages, as well as host cells in various tissues and organs, using single-cell and spatial sequencing applications. In recent years, this information has improved our understanding of trypanosomosis by deciphering the diverse populations of parasites in the developmental process, as well as the highly heterogeneous immune and tissue-resident cells involved in anti-trypanosome responses. Ultimately, the goal of these approaches is to gain an in-depth understanding of parasite biology and host immunity, potentially leading to new vaccination and therapeutic strategies against trypanosomosis.
2022-10-06 | Immunoinformatic design of a putative multi-epitope vaccine candidate against Trypanosoma brucei gambiense
Human African trypanosomiasis (HAT) is a neglected tropical disease that is caused by flagellated parasites of the genus Trypanosoma. HAT imposes a significant socio-economic burden on many countries in sub-Saharan Africa and its control is hampered by several drawbacks ranging from the ineffectiveness of drugs, complex dosing regimens, drug resistance, and lack of a vaccine. Despite more than a century of research and investigations, the development of a vaccine to tackle HAT is still challenging due to the complex biology of the pathogens. Advancements in computational modeling coupled with the availability of an unprecedented amount of omics data from different organisms have allowed the design of new generation vaccines that offer better antigenicity and safety profile. One of such new generation approaches is a multi-epitope vaccine (MEV) designed from a collection of antigenic peptides. A MEV can stimulate both cellular and humoral immune responses as well as avoiding possible allergenic reactions. Herein, we take advantage of this approach to design a MEV from conserved hypothetical plasma membrane proteins of Trypanosoma brucei gambiense, the trypanosome subspecies that is responsible for the west and central African forms of HAT. The designed MEV is 402 amino acids long (41.5 kDa). It is predicted to be antigenic, non-toxic, to assume a stable 3D conformation, and to interact with a key immune receptor. In addition, immune simulation foresaw adequate immune stimulation by the putative antigen and a lasting memory. Therefore, the designed chimeric vaccine represents a potential candidate that could be used to target HAT.
proteins
2026-06-01 | The bromodomain protein Bdf3 is sufficient to activate expression of a procyclin gene in bloodstream stage African trypanosomes.
The early-branching eukaryotic parasite, Trypanosoma brucei, lives extracellularly in the mammalian host, where it expresses variant surface glycoprotein (VSG). Antigenic variation of VSGs allows the parasite to evade the host immune response while in the bloodstream. Upon transition to the tsetse fly vector, the parasite remodels its surface to express procyclin protein from a limited set of EP and GPEET genes. While the environmental signals that trigger the switch from expressing VSG genes to expressing EP and GPEET genes are known, the molecular mechanism that initiates transcription of the EP and GPEET genes during parasite differentiation to the procyclic stage within the tsetse is not well understood. Previous work has shown that the chromatin-interacting bromodomain protein Bdf3 is absent from the RNA polymerase I promoter of the EP locus in bloodstream parasites, but appears there shortly after initiation of differentiation from the bloodstream to the procyclic stage. Here, we show that tethering of Bdf3 to the EP promoter using a dCas9-Bdf3 fusion protein and a guide RNA is sufficient to increase transcript levels of EP1 in bloodstream parasites, where the gene is normally silenced. This result supports the model that Bdf3 appears at the EP locus during differentiation to facilitate initiation of transcription, which is consistent with the role of Bdf3 as a transcriptional activator in other systems. Understanding gene regulatory mechanisms in this early-branching eukaryote may help build a more complete picture of the conserved and unique features of gene regulatory proteins across diverse biological systems. The Trypanosoma brucei parasite is transmitted via the tsetse fly vector to a mammalian host , where it causes African trypanosomiasis, a fatal disease that imposes a severe human and economic burden for people living in areas of sub-Saharan Africa. While drug treatments have improved for some strains, some infections still require treatment with drugs that have serious side effects. One avenue for drug development is to try to manipulate the life cycle of the parasite to make it poorly adapted to the mammalian host. However, this requires detailed knowledge of the mechanisms by which parasites regulate their genes as they progress through the life cycle. Here, we show that the DNA-interacting bromodomain protein Bdf3 may be a key driver for turning on insect-specific genes that code for insect-stage surface proteins. This finding could aid in the development of life cycle-manipulating drugs and shed light on how gene regulatory mechanisms evolved.
2025-12-31 | IL-10 Plays a Critical Role in Mitigating Acute Anaemia Development During African Trypanosome Infection.
During the first week of T. b. brucei infection, pro-inflammatory IFN-γ production drives acute anaemia by promoting red blood cell clearance by activated macrophages in concert with insufficient bone marrow compensation. The latter is followed by a partial recovery phase, which later progresses to chronic anaemia. To compensate for acute anaemia, stress-induced extramedullary erythropoiesis occurs in the spleen. However, the role of IL-10, a key anti-inflammatory cytokine in regulating stress-induced acute anaemia during African trypanosomosis (AT), remains unclear. Using both genetic and pharmacological approaches, we show that IL-10 is essential to limit acute anaemia by dampening inflammation and promoting splenic erythropoiesis, enabling recovery. More specifically, IL-10 blockade impairs erythropoiesis in both bone marrow and spleen, particularly at early erythroid differentiation stages, and associates with reduced central macrophage (CM) numbers in the bone marrow. In contrast, the co-inhibition of IL-10 and IFN-γ reduces inflammation and partially restores splenic CM numbers and erythropoiesis, highlighting IFN-γ's suppressive role in erythropoiesis. Overall, these findings underscore IL-10's key role in regulating stress-induced erythropoiesis during AT by modulating erythroid differentiation and CM abundance, thereby limiting immune-mediated acute anaemia. Consequently, timely adjustment of the IL-10/IFN-γ balance may enhance erythropoiesis and offer a potential therapeutic strategy to mitigate anaemia development.
2025-09-15 | Genome-wide overexpression screen reveals a novel transcription termination factor in Trypanosoma brucei.
Trypanosoma brucei is a protozoan parasite that causes African trypanosomiasis. We performed an overexpression library screen to gain insights into essential cellular processes in T. brucei and identified genes whose overexpression impaired parasite growth. One of the three top-ranking candidates we validated exhibited a notable phenotype. Tb FOP, an uncharacterized protein, has an N-terminal arginine-rich domain and a C-terminal FOP (Friend Of PRMT1) domain. Tb FOP overexpression substantially increases antisense transcription across the genome, particularly at Transcription Termination Sites (TTSs). This phenotype resembles that observed in trypanosome cells lacking a component of the transcription termination complex PJW/PP1 and cells lacking TTS chromatin marks, two histone variants, and base J DNA modification. Base J is synthesized in two steps: hydroxylation of dT to 5-hydroxymethyl-dU (5hmU) by JBP1 & JBP2, and the glucosylation of 5hmU to glucosyl-5hmU (base J) by JGT. Interestingly, human FOP interacts with 5-hydroxymethyl-dC (5hmC) generated by TET enzymes that are orthologs of T. brucei JBP1/2. Our study reveals Tb FOP as a novel transcription termination factor that may interact with TTS-associated 5hmU, thereby interfering with the function of termination factors. We propose that Tb FOP overexpression disrupts termination, leading to widespread transcription defects and trypanosome cell death.
2024-10-25 | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease.
Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.
2024-10-24 | Spiroplasma endosymbiont reduction of host lipid synthesis and Stomoxyn-like peptide contribute to trypanosome resistance in the tsetse fly Glossina fuscipes
Abstract Tsetse flies ( Glossina spp.) vector African trypanosomes that cause devastating diseases in humans and domestic animals. Within the Glossina genus, species in the Palpalis subgroup exhibit greater resistance to trypanosome infections compared to those in the Morsitans subgroup. Varying microbiota composition and species-specific genetic traits can significantly influence the efficiency of parasite transmission. Notably, infections with the endosymbiotic bacterium Spiroplasma have been documented in several Palpalis subgroup species, including Glossina fuscipes fuscipes ( Gff ). While Spiroplasma infections in Gff are known to hinder trypanosome transmission, the underlying mechanisms remain unknown. To investigate Spiroplasma- mediated factors affecting Gff vector competence, we conducted high-throughput RNA sequencing of the midgut tissue along with functional assays. Our findings reveal elevated oxidative stress in the midgut environment in the presence of Spiroplasma , evidenced by increased expression of nitric oxide synthase, which catalyzes the production of trypanocidal nitric oxide. Additionally, we observed impaired lipid biosynthesis leading to a reduction of this important class of nutrients essential for parasite and host physiologies. In contrast, trypanosome infections in Gff’s midgut significantly upregulated various immunity-related genes, including a small peptide, Stomoxyn-like , homologous to Stomoxyns first discovered in the stable fly Stomoxys calcitrans . We observed that the Stomoxyn-like locus is exclusive to the genomes of Palpalis subgroup tsetse species. Gff Stomoxyn is constitutively expressed in the cardia (proventriculus) and synthetic Gff Stomoxyn exhibits potent activity against Escherichia coli and bloodstream form of Trypanosoma brucei parasites, while showing no effect against insect stage procyclic forms or tsetse’s commensal endosymbiont Sodalis in vitro . Reducing Gff Stomoxyn levels significantly increased trypanosome infection prevalence, indicating its potential trypanocidal role in vivo . Collectively, our results suggest that the enhanced resistance to trypanosomes observed in Spiroplasma -infected Gff may be due to the reduced lipid availability necessary for parasite metabolic maintenance. Furthermore, Gff Stomoxyn could play a crucial role in the initial immune response(s) against mammalian parasites early in the infection process in the midgut and prevent gut colonization. We discuss the molecular characteristics of Gff Stomoxyn, its spatial and temporal expression regulation and its microbicidal activity against Trypanosome parasites. Our findings reinforce the nutritional influences of microbiota on host physiology and host-pathogen dynamics. Author Summary The tsetse fly, Glossina fuscipes fuscipes ( Gff ) is of high public health relevance. Gff exhibits strong innate resistance to trypanosomes, especially when infected with the endosymbiotic bacterium Spiroplasma . This study investigated how the bacterium Spiroplasma inside Gff enables them to be resistant to trypanosome infection. Our results indicate alterations in host lipid metabolism with reduction in levels of triglycerides, suggesting a potential metabolic barrier that limits the viability to parasite. In addition, we discovered a small peptide, stomoxyn, exclusively in Gff and related Palpalis tsetse species. We have shown that Gff synthetic Stomoxyn has antibacterial and antitrypanosomal properties and lowering Stomoxyn levels in Gff correlates with increased parasite prevalence. We suggest that strategies to increase Spiroplasma prevalence or enhance stomoxyn expression through paratransgenic approaches could be promising avenues for reducing trypanosomiasis transmission.
oligonucleotides
2026-09-07 | Immunoinformatics Approach for the Designing of a Novel mRNA Vaccine Candidate Against Trypanosoma brucei.
Trypanosoma brucei causes Human African Trypanosomiasis (HAT), which has a devastating impact on an individual's health. Currently, there is no FDA-approved vaccine for HAT prevention. Therefore, reverse vaccinology approaches were utilized to design an mRNA vaccine candidate. Variant surface glycoprotein, heat shock protein 70, and vacuolar transporter chaperone complex of T. brucei were targeted to predict immunogenic, non-allergenic, and non-toxic peptides. The vaccine candidate was evaluated for population coverage, biophysical attributes, structural stability, and refinement. Molecular docking, MD simulation, and MM-GBSA analyses evaluate receptor binding and complex stability. Codon optimization and in-silico cloning were conducted in Escherichia coli (strain K12) using pET-28a( +). Immune simulations predicted humoral and cellular responses, while mRNA integrity was evaluated through MFE analysis. The vaccine candidate achieved 100% global population coverage. Biophysical attributes indicated aliphaticity 71.23, and GRAVY score -0.719. Predicted tertiary structure (TM-score 0.65 ± 0.13, and C-score -0.50) was refined with stable validation metrics (Ramachandran score 86.8%, and Z-score -5.26). Docking predicted significant binding with TLR-2 and TLR-4 (energy scores -1013.5 and -1002.8 kJ/mol), validated through MD simulation, PCA, DCCM, MM-GBSA analyses. Codon optimization (CAI 0.9688; GC 44.70%) indicated high expression potential, and immune simulation exhibits robust antibody and cell-mediated responses, including elevated B lymphocyte, T lymphocyte levels, and IgM, IgG titers. Finally, the structural integrity of mRNA was predicted by MFE values. This in-silico designed vaccine demonstrated strong structural stability, receptor interactions, and immunogenic potential against T. brucei. Experimental validation and in-vivo studies are required to verify safety and efficacy of vaccine candidate.
2026-05-24 | Aptamers as immunomodulatory therapeutic alternatives targeting neglected tropical diseases (NTDs).
Neglected tropical diseases (NTDs) comprise a heterogeneous group of infections that disproportionately affect populations in low- and middle-income countries, where limited access to diagnostics, therapeutics, and surveillance perpetuates disease burden. Conventional strategies based on antibodies and small-molecule drugs face major challenges, including high production costs, limited stability, cross-reactivity, toxicity, and the emergence of drug resistance. In this context, aptamers, short single-stranded nucleic acids selected by SELEX, have emerged as versatile immunomodulatory tools with significant potential for the diagnosis and treatment of NTDs. This chapter provides a comprehensive overview of aptamer-based strategies targeting major NTDs, with particular emphasis on human African trypanosomiasis and arboviral infections such as dengue, Zika, and chikungunya. Aptamers directed against conserved parasite and viral epitopes demonstrate the capacity to circumvent immune evasion mechanisms, including antigenic variation and serotype diversity, while enabling highly specific recognition and internalization. In African trypanosomes, RNA aptamers targeting variant surface glycoproteins exploit the flagellar pocket for targeted drug delivery, offering a novel approach to overcome therapeutic resistance. In arboviral diseases, aptamers have been successfully integrated into advanced diagnostic platforms, including competitive ELISA, electrochemical, and capacitive biosensors, achieving high sensitivity, rapid response times, and minimal cross-reactivity among closely related flaviviruses. Beyond diagnostics, selected aptamers exhibit neutralizing activity and immunomodulatory effects by interfering with host-pathogen interactions and innate immune signaling pathways.
2025-10-09 | DNA Vaccine Encoding Trypanosoma brucei MSP-B Elicited IgG and IFN-γ Responses and Partial Protection in Immunised Mice.
As an effort towards vaccine development against African trypanosomiasis, we studied key parasite molecules that mediate VSG functions, specifically the major surface protease-B of Trypanosoma brucei that catalyses proteolytic removal of old VSGs for expression of new ones, an important stage-specific function that allows the parasite to survive in its host, thus making it an attractive candidate for vaccine development. Herein, the Tbmsp-b gene was cloned into a pVAX-1 plasmid to produce the pVAX-1-Tbmsp-b construct for DNA vaccine trials. BALB/c mice were immunised by intradermal injection with a 100 μg dose of the construct thrice on Days 0, 21 and 42, then inoculated with 2000 parasites on Day 56. Anti-trypanosome-specific antibody (IgG) and cytokine (IFN-γ) were monitored by ELISA from sera of immunised and unimmunised mice. Immunised mice showed significantly (p < 0.05) higher IgG and IFN-γ responses, lower parasitaemia (by 75% and 51.2% of parasitaemic scores on the first and fifth week of infection) and longevity by up to 22 days compared to unimmunised mice. These results showed that the construct provided partial protection to virulent T. b. brucei (Federe strain) infection in susceptible BALB/c mice, suggesting the potential for using MSP-B as an antigen in DNA vaccine development against African trypanosomiasis.
2025-07-15 | Current Status and Prospects for Development of a Vaccine against African Trypanosoma: A Review
Background: African trypanosomiasis, a disease caused by Trypanosoma brucei, remains a significant health challenge in sub-Saharan Africa, particularly in rural communities with limited healthcare access. Despite control efforts, the disease persists due to the parasite's complex immune evasion mechanisms, including antigenic variation and destruction of the host's humoral immune response. Current treatments face limitations, and the development of an effective vaccine is stalled by the parasite's genetic diversity and insufficient research funding. Objective: This review aimed to compile recent advancements in vaccine development against African trypanosomiasis, evaluate potential vaccine candidates, and identify challenges and future directions for developing an effective vaccine. Method: We adopted the PRISMA protocol to guide our systematic literature on Medline/PubMed and Google Scholar databases, focusing on studies published between 2005 and April 2025. Results: The findings revealed several encouraging approaches to vaccine development against African trypanosomiasis. DNA vaccines targeting specific parasite proteins have demonstrated partial protection in animal studies, stimulating immune responses that delay disease progression. The T. brucei membrane surface protein B (Tbmsp-b) gene was cloned into a pVAX-1 plasmid and administered into a BALB/c mice model, conferring partial protection. Similarly, DNA plasmid encoding an invariant surface glycoprotein (ISG) of T. brucei provided partial protection against T. brucei in the BALB/c mice model. Plasmid DNA containing the 5′-terminal region of the T. brucei brucei trans-sialidase (nTSA) gene also provided partial protection in BALB/c mice. Innovative computer-designed vaccines, which combine multiple T. brucei epitopes, showed particular promise against the parasite's variability in terms of antigenicity.
2022-08-15 | Oligo targeting for profiling drug resistance mutations in the parasitic trypanosomatids.
Trypanosomatids cause the neglected tropical diseases, sleeping sickness, Chagas disease and the leishmaniases. Studies on these lethal parasites would be further facilitated by new and improved genetic technologies. Scalable precision editing methods, for example, could be used to improve our understanding of potential mutations associated with drug resistance, a current priority given that several new anti-trypanosomal drugs, with known targets, are currently in clinical development. We report the development of a simple oligo targeting method for rapid and precise editing of priority drug targets in otherwise wild type trypanosomatids. In Trypanosoma brucei, approx. 50-b single-stranded oligodeoxynucleotides were optimal, multiple base edits could be incorporated, and editing efficiency was substantially increased when mismatch repair was suppressed. Resistance-associated edits were introduced in T. brucei cyclin dependent kinase 12 (CRK12, L482F) or cleavage and polyadenylation specificity factor 3 (N232H), in the Trypanosoma cruzi proteasome β5 subunit (G208S), or in Leishmania donovani CRK12 (G572D). We further implemented oligo targeting for site saturation mutagenesis, targeting codon G492 in T. brucei CRK12. This approach, combined with amplicon sequencing for codon variant scoring, revealed fourteen resistance conferring G492 edits encoding six distinct amino acids. The outputs confirm on-target drug activity, reveal a variety of resistance-associated mutations, and facilitate rapid assessment of potential impacts on drug efficacy.
other
2026-09-10 | Friends or foes: Unraveling the tsetse fly-Spiroplasma symbiosis.
Tsetse flies (Glossina spp.) transmit African trypanosomes, the causative agents of human African and African animal trypanosomiases (HAT and AAT, respectively). These neglected tropical diseases impose significant public health and economic burdens across sub-Saharan Africa. Trypanosome transmission by tsetse flies is influenced by multiple factors, including host genetic background, ecological factors, and interactions with heritable microbial endosymbionts. Spiroplasma glossinidia has recently emerged as an important modulator of tsetse reproductive fitness and vector competence, making it a potential target for symbiont-based vector control strategies. In this review, we summarize the current knowledge of the tsetse-Spiroplasma symbiosis. We detail Spiroplasma's spatial and temporal infection dynamics in laboratory-reared and natural populations. Additionally, we highlight key aspects of the bacterium's genomics, phylogenetics, and physiological interactions with its tsetse host, including influences on host gene expression reproductive physiology, and vector competence. Finally, we discuss how the tsetse-Spiroplasma symbiosis could be harnessed to develop innovative, biological-based vector control and trypanosome transmission-blocking strategies, and we identify critical gaps that must be addressed to translate these findings into effective disease control interventions.
2026-03-27 | Germline-targeted baboon apolipoprotein L-1 protects mice against African trypanosomes.
Some primates are immune to infection by most African trypanosome parasites due to apolipoprotein L-1 (APOL1), a primate-specific ion channel-forming protein. Our long-term objective has been to reduce African trypanosomiasis in livestock by genetic bioengineering of cattle with primate APOL1. To select which primate APOL1, we analyzed Papio ssp. APOL1 proteins and found that Papio hamadryas APOL1 was a strong candidate for transgenic animal production based on its trypanosome-killing capacity, ion channel properties, and stability. We generated seven transgenic murine lines based on the P. hamadryas APOL1 sequence and used these mice to investigate the level of APOL1 expression required for trypanosome immunity in vivo. We challenged the murine lines with three human and four livestock trypanosome isolates. P. hamadryas APOL1 provided protection against all of the human and three of the livestock trypanosome isolates, though not against Trypanosoma vivax despite the logical hypothesis that APOL1 plays a role in primate immunity to that parasite. Occasionally, lower APOL1 expression in heterozygote mice selected for the emergence of APOL1 resistant parasites in several trypanosome spp. Alarmingly, these resistant parasites were also resistant to high levels of APOL1 in homozygous mice, indicating an increase in virulence. A more-highly expressed chimeric APOL1 transgene encoding Homo sapiens APOL1 with the P. hamadryas APOL1 C-terminus was more effectively protective in heterozygote mice; however, we could not produce homozygous mice, suggesting endogenous toxicity to the mice. Together, these data bear relevance to our long-term objective to generate transgenic APOL1 cattle, the feasibility of which is discussed.
2026-03-16 | Dual faces of γδ T cells in trypanosomatid infections.
In this review, we tell the story of how two related parasites that belong to the same genus, Trypanosoma brucei and Trypanosoma cruzi, cause very distinct lethal diseases and how γδ T cells help shape these outcomes. It synthesizes current knowledge on γδ T-cell responses to T. brucei and T. cruzi, highlighting shared and parasite-specific features. Here we emphasize how γδ T-cell cytotoxic versus regulatory programs and tissue residency in blood, lymphoid organs, liver, gut, heart, and skin influence early parasite control, chronic persistence, and immunopathology. Finally, we discuss the gaps that need to be filled and how these insights may inform new interventions, including modulation of γδ function, γδ-targeted vaccine strategies, and γδ-based biomarkers for host-directed therapies in Chagas disease and human African trypanosomiasis.
2025-10-20 | Cure of experimental Trypanosoma vivax infection with a single dose of an unmodified antibody-based drug targeting the invariant flagellum cell surface protein IFX.
Animal African trypanosomiasis (AAT) is an infectious wasting disease of economically important livestock caused by Trypanosoma spp. parasites. The disease is primarily caused by two species: Trypanosoma congolense and Trypanosoma vivax, which are endemic in many African countries. AAT is managed by therapeutic and prophylactic drugs; however, resistance is now widely reported, and the development of new drugs has been impeded due to a chronic lack of investment. Recently, we identified an invariant flagellar-associated cell surface protein (IFX) that could elicit protective immune responses when used as a vaccine against T. vivax. We showed that a complement-recruiting anti-IFX monoclonal antibody can prevent infection when used prophylactically. Here, we show that this same unmodified antibody can be used to cure T. vivax infections in a murine experimental model. Importantly, we show that infections can be treated with a single dose and demonstrate full cure by the lack of detectable parasites in peripheral tissues even after immunosuppression. Using structural modeling and site-directed mutagenesis, we localize the protective antibody epitope, thereby identifying targetable regions on IFX to improve vaccine design. Together, these findings validate IFX as both a prophylactic and curative drug target that could be useful in the management of AAT.IMPORTANCETrypanosoma vivax is a parasite that causes animal African trypanosomiasis (AAT), a chronic wasting disease that infects economically important livestock animals, which is a particular problem in African countries south of the Sahara. The impact of this disease is significant: it is responsible for over 3 million cattle deaths and an estimated $4.5 billion of annual lost productivity. There is a desperate need to develop new control measures because resistance is now widely reported to the drugs commonly used to treat this infection. We show here that a single dose of an unmodified monoclonal antibody that recognizes IFX-a parasite cell surface protein localized to the flagellum-is sufficient to cure an established T. vivax infection with no parasite reservoirs detectable in peripheral tissues. Our finding validates IFX as a new drug target and provides a rationale route to the development of new drugs to target AAT.
2025-09-10 | Molecular Detection and Phylogenetic Characterization of Wolbachia Strains in Glossina Species from Nigerian Conservation Areas
Tsetse flies (Glossina spp.), the vectors of human and animal African trypanosomiasis, continue to exert a profound toll on public health and livestock productivity in Nigeria. This study investigates the prevalence, seasonal dynamics, and genetic diversity of Wolbachia endosymbionts in 7,632 wild-caught tsetse flies sampled from four ecologically distinct conservation sites: Yankari Game Reserve, Kainji Lake National Park, Kagarko Forest, and Ijah Gwari Forest. Molecular screening based on wsp gene sequencing detected Wolbachia in 1,771 flies, with infection rates rising significantly during the wet season (e.g., G. morsitans submorsitans: 75.4% vs. 39.8% in dry season; p < 0.001). Female flies showed consistently higher infection prevalence, reinforcing the role of vertical transmission. Phylogenetic reconstruction revealed nine Wolbachia strains spanning supergroups A and B, including a putatively unique regional variant (wsp9) restricted to northern Nigeria. Bacterial load exhibited a strong age-dependent pattern (r = 0.912, p < 0.001), and elevated GC content (~ 63%) suggested possible adaptation to savanna thermal conditions. These findings highlight the ecological flexibility of Wolbachia within natural tsetse populations and point to its potential application in vector control—particularly through mechanisms like cytoplasmic incompatibility. By combining molecular detection, ecological data, and evolutionary analysis, this study lays the groundwork for tailored, climate-sensitive Wolbachia-based strategies to reduce tsetse populations and support trypanosomiasis control in Nigeria.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for African trypanosomiasis, including 2 approved therapies.
6 orphan drug designations for African trypanosomiasis, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
suramin | small molecules | FDA | — | PaxMedica, Inc. |
fexinidazole | small molecules | FDA | Approved | Sanofi US Services Inc., A SANOFI COMPANY |
melarsoprol-hydroxypropylbetadex | small molecules | FDA | Peter Kennedy, CBE, MD, PhD, DSc, FRCP FMedSci, | |
Melarsoprol | small molecules | EMA | Stéphane Gibaud | |
Pafuramidine maleate | small molecules | FDA | Immtech Pharmaceuticals, Inc. | |
Eflornithine HCl [Ornidyl] | small molecules | FDA | Approved | Hoechst Marion Roussel |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.