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JAMA May 2024
Topics: Animals; Humans; Mice; Apolipoprotein L1; Kidney Diseases; Black or African American; United States; Renal Insufficiency, Chronic; Gene Frequency; Black People; Genetic Testing; Africa South of the Sahara; Caribbean Region; Central America; South America; Trypanosomiasis, African
PubMed: 38662391
DOI: 10.1001/jama.2024.2667 -
Virulence Dec 2023African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South... (Review)
Review
African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South America. In humans, infection is caused by variants of , and is characterized by varying rate of progression to neurological disease, caused by parasites exiting the vasculature and entering the brain. Animal disease is caused by multiple species of trypanosome, primarily , and . These trypanosomes also infect multiple species of mammalian host, and this complexity of trypanosome and host diversity is reflected in the spectrum of severity of disease in animal trypanosomiasis, ranging from hyperacute infections associated with mortality to long-term chronic infections, and is also a main reason why designing interventions for animal trypanosomiasis is so challenging. In this review, we will provide an overview of the current understanding of trypanosome determinants of infection progression and severity, covering laboratory models of disease, as well as human and livestock disease. We will also highlight gaps in knowledge and capabilities, which represent opportunities to both further our fundamental understanding of how trypanosomes cause disease, as well as facilitating the development of the novel interventions that are so badly needed to reduce the burden of disease caused by these important pathogens.
Topics: Animals; Humans; Trypanosomiasis, African; Virulence; Tsetse Flies; Trypanosoma; Trypanosomiasis; Mammals
PubMed: 36419235
DOI: 10.1080/21505594.2022.2150445 -
Future Medicinal Chemistry Aug 2023Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries, making the need for novel...
Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries, making the need for novel drugs urgent. Therefore, an explainable multitask pipeline to profile the activity of compounds against three trypanosomes ( and ) were created. These models successfully discovered four new experimental hits (, , and ). Among them, showed promising results, with IC values ranging 0.01-0.072 μM and selectivity indices >10,000. These results demonstrate that the multitask protocol offers predictivity and interpretability in the virtual screening of new antitrypanosomal compounds and has the potential to improve hit rates in Chagas and human African trypanosomiasis projects.
Topics: Animals; Humans; Trypanosomiasis, African; Trypanocidal Agents; Chagas Disease; Trypanosoma brucei brucei; Trypanosoma cruzi
PubMed: 37701989
DOI: 10.4155/fmc-2023-0074 -
Nature Communications Jul 2023African trypanosomes are dixenous eukaryotic parasites that impose a significant human and veterinary disease burden on sub-Saharan Africa. Diversity between species and...
African trypanosomes are dixenous eukaryotic parasites that impose a significant human and veterinary disease burden on sub-Saharan Africa. Diversity between species and life-cycle stages is concomitant with distinct host and tissue tropisms within this group. Here, the spatial proteomes of two African trypanosome species, Trypanosoma brucei and Trypanosoma congolense, are mapped across two life-stages. The four resulting datasets provide evidence of expression of approximately 5500 proteins per cell-type. Over 2500 proteins per cell-type are classified to specific subcellular compartments, providing four comprehensive spatial proteomes. Comparative analysis reveals key routes of parasitic adaptation to different biological niches and provides insight into the molecular basis for diversity within and between these pathogen species.
Topics: Humans; Animals; Trypanosomiasis, African; Tsetse Flies; Proteome; Proteomics; Trypanosoma brucei brucei; Trypanosoma congolense
PubMed: 37479728
DOI: 10.1038/s41467-023-40125-z -
QJM : Monthly Journal of the... Jun 2024
Review
Topics: Humans; Trypanosomiasis, African; Trypanocidal Agents
PubMed: 38917478
DOI: 10.1093/qjmed/hcae106 -
Trends in Parasitology Dec 2023African trypanosomes show a remarkable ability to survive as extracellular parasites in the blood and tissue spaces of an infected mammal. Throughout the infection they... (Review)
Review
African trypanosomes show a remarkable ability to survive as extracellular parasites in the blood and tissue spaces of an infected mammal. Throughout the infection they are exposed to the molecules and cells of the immune system, including complement. In this opinion piece, we review decades-worth of evidence about how complement affects African trypanosomes. We highlight the discovery of a trypanosome receptor for complement C3 and we critically assess three recent studies which attempt to provide a structural and mechanistic view of how this receptor helps trypanosomes to survive in the presence of complement.
Topics: Animals; Trypanosoma; Trypanosomiasis, African; Mammals
PubMed: 37758633
DOI: 10.1016/j.pt.2023.09.001 -
Nature Communications Jul 2023Replication Protein A (RPA) is a broadly conserved complex comprised of the RPA1, 2 and 3 subunits. RPA protects the exposed single-stranded DNA (ssDNA) during DNA...
Replication Protein A (RPA) is a broadly conserved complex comprised of the RPA1, 2 and 3 subunits. RPA protects the exposed single-stranded DNA (ssDNA) during DNA replication and repair. Using structural modeling, we discover an inhibitor, JC-229, that targets RPA1 in Trypanosoma brucei, the causative parasite of African trypanosomiasis. The inhibitor is highly toxic to T. brucei cells, while mildly toxic to human cells. JC-229 treatment mimics the effects of TbRPA1 depletion, including DNA replication inhibition and DNA damage accumulation. In-vitro ssDNA-binding assays demonstrate that JC-229 inhibits the activity of TbRPA1, but not the human ortholog. Indeed, despite the high sequence identity with T. cruzi and Leishmania RPA1, JC-229 only impacts the ssDNA-binding activity of TbRPA1. Site-directed mutagenesis confirms that the DNA-Binding Domain A (DBD-A) in TbRPA1 contains a JC-229 binding pocket. Residue Serine 105 determines specific binding and inhibition of TbRPA1 but not T. cruzi and Leishmania RPA1. Our data suggest a path toward developing and testing highly specific inhibitors for the treatment of African trypanosomiasis.
Topics: Animals; Humans; Trypanosoma brucei brucei; Trypanosomiasis, African; Replication Protein A; DNA Replication; DNA, Single-Stranded; Chagas Disease; Protein Binding
PubMed: 37474515
DOI: 10.1038/s41467-023-39839-x -
Microorganisms Sep 2023Blood and tissue protozoan infections are responsible for an enormous burden in tropical and subtropical regions, even though they can also affect people living in... (Review)
Review
Blood and tissue protozoan infections are responsible for an enormous burden in tropical and subtropical regions, even though they can also affect people living in high-income countries, mainly as a consequence of migration and travel. These pathologies are responsible for heavy socio-economic issues in endemic countries, where the lack of proper therapeutic interventions and effective vaccine strategies is still hampering their control. Moreover, the pathophysiological mechanisms associated with the establishment, progression and outcome of these infectious diseases are yet to be fully described. Among all the players, extracellular vesicles (EVs) have raised significant interest during the last decades due to their capacity to modulate inter-parasite and host-parasite interactions. In the present manuscript, we will review the state of the art of circulating host-derived EVs in clinical samples or in experimental models of human blood and tissue protozoan diseases (i.e., malaria, leishmaniasis, Chagas disease, human African trypanosomiasis and toxoplasmosis) to gain novel insights into the mechanisms of pathology underlying these conditions and to identify novel potential diagnostic markers.
PubMed: 37764162
DOI: 10.3390/microorganisms11092318 -
QJM : Monthly Journal of the... Jun 2024Human African trypanosomiasis (HAT), or sleeping sickness, continues to be a major threat to human health in 36 countries throughout sub-Saharan Africa with up to 60... (Review)
Review
Human African trypanosomiasis (HAT), or sleeping sickness, continues to be a major threat to human health in 36 countries throughout sub-Saharan Africa with up to 60 million people at risk. Over the last decade, there have been several advances in this area, some of which are discussed in this overview. Due to the concerted efforts of several bodies, including better identification and treatment of cases and improved tsetse fly vector control, the number of cases of HAT has declined dramatically. The clinical heterogeneity of HAT has also been increasingly recognized, and the disease, while usually fatal if untreated or inadequately treated, does not always have a uniformly fatal outcome. Improved methods of HAT diagnosis have now been developed including rapid diagnostic tests. Novel drug treatment of HAT has also been developed, notably nifurtimox-eflornithine combination therapy (NECT) for late-stage Trypanosoma brucei gambiense, oral fexinidazole for early and the early component of the late-stage of T.b. gambiense, and the new oral compounds of the oxaborole group, which have shown considerable promise in field trials. Advances in HAT neuropathogenesis have been steady, though largely incremental, with a particular focus on the role of the blood-brain barrier in parasite entry into the central nervous system and the relevant importance of both innate and adaptive immunity. While the World Health Organization goal of elimination of HAT as a public health problem by 2020 has probably been achieved, it remains to be seen whether the second more ambitious goal of interruption of transmission of HAT by 2030 will be attained.
Topics: Trypanosomiasis, African; Humans; Trypanocidal Agents; Trypanosoma brucei gambiense; Animals; Africa South of the Sahara; Tsetse Flies; Nifurtimox; Blood-Brain Barrier; Eflornithine
PubMed: 38065835
DOI: 10.1093/qjmed/hcad273 -
Pathogens (Basel, Switzerland) Jan 2024Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or... (Review)
Review
Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.
PubMed: 38251386
DOI: 10.3390/pathogens13010079