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PLoS Neglected Tropical Diseases Jun 2024Yaws, caused by Treponema pallidum ssp. pertenue, remains a significant public health concern in tropical regions of West Africa and the South Pacific, primarily...
Yaws, caused by Treponema pallidum ssp. pertenue, remains a significant public health concern in tropical regions of West Africa and the South Pacific, primarily affecting children in remote areas with limited access to hygiene and sanitation. In this study, conducted in three endemic countries of West Africa where yaws remains a significant public health concern (Ghana, Cameroon, and Côte d'Ivoire), we aimed to assess the knowledge, attitudes, and practices related to yaws among community members, community health workers (CHWs), and traditional healers. The study revealed variations in the perception of causes of yaws among community members: the majority or participants in Ghana attributed yaws to germs (60.2%); in Cameroon the most reported form of transmission was contact with or drinking infected water sources (44.6%); and in Côte d'Ivoire both of these answers were also the most prevalent (60.3% germs and 93.% water sources). A substantial proportion of participants in Côte d'Ivoire also associated yaws with witchcraft and divine punishment (44.8%). Only a small proportion of individuals in Ghana and Côte d'Ivoire correctly identified contact with an infected person as a form of transmission (11.9% and 20.7%, respectively) and less than half in Cameroon (42.6%), although more than 98% of all participants reported avoidance behaviours towards yaws infected people due to fear of getting infected. Most participants expressed a preference for seeking care at hospitals (49.2%, 60.6%, 86.2%) or health care professionals including doctors and nurses (58.5%, 41,5% and 17.2%) if they were diagnosed with yaws, although a quarter of participants in Côte d'Ivoire also sought support from traditional healers. The CHWs interviewed were generally well-trained on yaws causes and treatment options, although they often reported low availability of treatment and diagnostic tests for yaws. Our findings underscore the need for community education, awareness campaigns, ongoing CHW training, and improved access to yaws treatment and diagnostic resources. The data also suggest that collaboration with traditional healers, who usually hold a highly esteemed position in the society, such as giving training on yaws causes and transmission or exchanging knowledge on treatment options, could be beneficial in certain regions, particularly in Côte d'Ivoire.
PubMed: 38900827
DOI: 10.1371/journal.pntd.0012224 -
Medecine Tropicale Et Sante... Mar 2024Tsetse flies are obligate bloodfeeders that occur exclusively in Sub-Saharan Africa, where they are the vectors of trypanosomes causing HAT (human African...
BACKGROUND - RATIONALE
Tsetse flies are obligate bloodfeeders that occur exclusively in Sub-Saharan Africa, where they are the vectors of trypanosomes causing HAT (human African trypanosomiasis) and AAT (African animal trypanosomiasis). In Chad, tsetse flies occur only in the most southern part of the country because of its favorable bioclimatic conditions. However, despite the importance of HAT and AAT in this country, very little is known about the current tsetse distribution, in particular its northern limit, which is of key importance for the surveillance of these diseases.
MATERIAL AND METHODS - RESULTS
A total of 217 biconical traps were deployed in 2021 and 2022 from the West to the East around the formerly known northern limit, resulting in 1,024 tsetse caught belonging to three different taxa: (57%), (39%) and (4%). In addition to the information gathered on the presence/absence of each tsetse taxon, we show a strong North-South shift of the northen tsetse distribution limit as compared to the previous works from 1966 to 1996, and a growing spatial fragmentation in more and more discrete pockets of tsetse presence.
DISCUSSION - CONCLUSION
This North-South shift of the northern tsetse distribution limit in Chad is the likely consequence of the combined effect of severe draughts that affected the country, and increasing human pressure on land. This update of the tsetse northern limit will be of help to the national programmes in charge of HAT and AAT.
Topics: Chad; Tsetse Flies; Animals; Animal Distribution; Climate Change; Humans; Insect Vectors
PubMed: 38846117
DOI: 10.48327/mtsi.v4i1.2024.392 -
Bioorganic & Medicinal Chemistry Letters May 2024Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is...
Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.
PubMed: 38823730
DOI: 10.1016/j.bmcl.2024.129825 -
Molecules (Basel, Switzerland) May 2024Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected... (Review)
Review
Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for and viability.
Topics: NADH, NADPH Oxidoreductases; Humans; Amide Synthases; Trypanosoma; Glutathione; Animals; Spermidine; Leishmania; Trypanocidal Agents; Leishmaniasis; Trypanosomatina; Protozoan Proteins; Chagas Disease
PubMed: 38792079
DOI: 10.3390/molecules29102214 -
Bioorganic & Medicinal Chemistry Jun 2024In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT)....
In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated ICs in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.
Topics: Animals; Trypanosoma brucei brucei; Trypanocidal Agents; Structure-Activity Relationship; Mice; Humans; Administration, Oral; Cell Proliferation; Molecular Structure; Molecular Docking Simulation; Tubulin; Parasitic Sensitivity Tests; Dose-Response Relationship, Drug; Tubulin Modulators; Trypanosomiasis, African
PubMed: 38762979
DOI: 10.1016/j.bmc.2024.117751 -
Sleep Advances : a Journal of the Sleep... 2024In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of...
In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of investigations in cats, I obtained my medical doctorate. Being a military physician, I was posted to Antarctica for wintering over and was initiated by Jean Rivolier into the psychology of small isolated human groups. I recorded 180 polysomnographic (PSG) nights in eight of my companions. This was my first contribution to research on human sleep under extreme environments and conditions. I then entered René Hénane's military thermophysiology laboratory, where I analyzed thermal exchanges during human sleep in the heat. Back to the cold, I spent 2 years in Canada and analyzed sleep during the Arctic winter under the direction of Manny W. Radomski, who headed the Defense and Civil Institute of Environmental Medicine and judged my PhD dissertation along with my first two mentors. Throughout my career, I worked in collaboration with Manny Radomski under the auspices of the Franco-Canadian Accord for Defence Research. We studied sleep and exercise, sleep deprivation, and recovery with and without chemical help. He also gave me support during several investigations in Africa. There, I studied normal sleep under various tropical climates (warm and dry in Niger, warm and humid in Côte d'Ivoire and Congo, temperate mid-mountain in Angola). I determined that human African trypanosomiasis, the ravaging sleeping sickness or tsetse disease, is not a hypersomnia, but a disorder of circadian rhythms, notably in the sleep-wake cycle.
PubMed: 38737795
DOI: 10.1093/sleepadvances/zpae025 -
Parasites & Vectors May 2024Animal African trypanosomiasis, which is caused by different species of African trypanosomes, is a deadly disease in livestock. Although African trypanosomes are often...
BACKGROUND
Animal African trypanosomiasis, which is caused by different species of African trypanosomes, is a deadly disease in livestock. Although African trypanosomes are often described as blood-borne parasites, there have been recent reappraisals of the ability of these parasites to reside in a wide range of tissues. However, the majority of those studies were conducted on non-natural hosts infected with only one species of trypanosome, and it is unclear whether a similar phenomenon occurs during natural animal infections, where multiple species of these parasites may be present.
METHODS
The infective trypanosome species in the blood and other tissues (adipose and skin) of a natural host (cows, goats and sheep) were determined using a polymerase chain reaction-based diagnostic.
RESULTS
The animals were found to harbour multiple species of trypanosomes. Different patterns of distribution were observed within the host tissues; for instance, in some animals, the blood was positive for the DNA of one species of trypanosome and the skin and adipose were positive for the DNA of another species. Moreover, the rate of detection of trypanosome DNA was highest for skin adipose and lowest for the blood.
CONCLUSIONS
The findings reported here emphasise the complexity of trypanosome infections in a natural setting, and may indicate different tissue tropisms between the different parasite species. The results also highlight the need to include adipose and skin tissues in future diagnostic and treatment strategies.
Topics: Animals; Goats; Trypanosomiasis, African; Adipose Tissue; Trypanosoma; Skin; Sheep; Goat Diseases; Cattle; Polymerase Chain Reaction; Sheep Diseases; DNA, Protozoan; Cattle Diseases
PubMed: 38734633
DOI: 10.1186/s13071-024-06277-7 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current...
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the , 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against and parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the -substituted BODIPY, with 1-dimethylaminonaphthalene () and anthracene moiety (), were the most active against , displaying IC = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues and exhibited the highest toxicity (IC = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against . Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Topics: Boron Compounds; Trypanosoma brucei brucei; Humans; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania major; Drug Design; Structure-Activity Relationship; Cell Line; Molecular Structure; Trypanocidal Agents; Oxidoreductases
PubMed: 38731562
DOI: 10.3390/molecules29092072 -
PLoS Neglected Tropical Diseases May 2024Sleeping sickness caused by Trypanosoma brucei rhodesiense is a fatal disease and endemic in Southern and Eastern Africa. There is an urgent need to develop novel...
BACKGROUND
Sleeping sickness caused by Trypanosoma brucei rhodesiense is a fatal disease and endemic in Southern and Eastern Africa. There is an urgent need to develop novel diagnostic and control tools to achieve elimination of rhodesiense sleeping sickness which might be achieved through a better understanding of trypanosome gene expression and genetics using endemic isolates. Here, we describe transcriptome profiles and population structure of endemic T. b. rhodesiense isolates in human blood in Malawi.
METHODOLOGY
Blood samples of r-HAT cases from Nkhotakota and Rumphi foci were collected in PaxGene tubes for RNA extraction before initiation of r-HAT treatment. 100 million reads were obtained per sample, reads were initially mapped to the human genome reference GRCh38 using HiSat2 and then the unmapped reads were mapped against Trypanosoma brucei reference transcriptome (TriTrypDB54_TbruceiTREU927) using HiSat2. Differential gene expression analysis was done using the DeSeq2 package in R. SNP calling from reads that were mapped to the T. brucei genome was done using GATK in order to identify T.b. rhodesiense population structure.
RESULTS
24 samples were collected from r-HAT cases of which 8 were from Rumphi and 16 from Nkhotakota foci. The isolates from Nkhotakota were enriched with transcripts for cell cycle arrest and stumpy form markers, whereas isolates in Rumphi focus were enriched with transcripts for folate biosynthesis and antigenic variation pathways. These parasite focus-specific transcriptome profiles are consistent with the more virulent disease observed in Rumphi and a less symptomatic disease in Nkhotakota associated with the non-dividing stumpy form. Interestingly, the Malawi T.b. rhodesiense isolates expressed genes enriched for reduced cell proliferation compared to the Uganda T.b. rhodesiense isolates. PCA analysis using SNPs called from the RNAseq data showed that T. b. rhodesiense parasites from Nkhotakota are genetically distinct from those collected in Rumphi.
CONCLUSION
Our results suggest that the differences in disease presentation in the two foci is mainly driven by genetic differences in the parasites in the two major endemic foci of Rumphi and Nkhotakota rather than differences in the environment or host response.
Topics: Malawi; Humans; Trypanosoma brucei rhodesiense; Transcriptome; Trypanosomiasis, African; Gene Expression Profiling; Polymorphism, Single Nucleotide; Male
PubMed: 38701067
DOI: 10.1371/journal.pntd.0011516 -
The American Journal of Tropical... Jun 2024Animal African trypanosomiasis, also known as nagana, is caused by Trypanosoma species, which cause significant clinical diseases and lead to losses in animal...
Animal African trypanosomiasis, also known as nagana, is caused by Trypanosoma species, which cause significant clinical diseases and lead to losses in animal production. We carried out a cross-sectional survey to investigate the composition of vectors and parasite diversity in two districts in the eastern region of Ghana where pigs and cattle were exposed to tsetse bites. We performed cytochrome c oxidase subunit 1 polymerase chain reaction (PCR) to identify tsetse species and internal transcribed spacer 1 PCR to identify Trypanosoma species. Also, we investigated the source of tsetse blood meal based on mitochondrial cytochrome b gene sequence analysis. A total of 229 tsetse, 65 pigs, and 20 cattle were investigated for trypanosomes. An overall vector density of 4.3 tsetse/trap/day was observed. A trypanosome prevalence of 58.9% (95% CI = 52.5-65.1%), 46.2% (95% CI = 34.6-58.1%), and 0.0% (95% CI = 0.0-16.1%) in tsetse, pigs, and cattle, respectively, was detected. Trypanosoma congolense was predominant, with a prevalence of 33.3% (95% CI = 73.3-86.5%) in tsetse. There was evidence of multiple infections in tsetse and pigs. Approximately 39% of the tsetse were positive for multiple infections of T. congolense and Trypanosoma simiae. Parasite prevalence in pigs across the communities was high, with significant differences associated between locations (χ2 = 28.06, 95% CI = 0.05-0.81, P = 0.0009). Tsetse blood meal analysis revealed feeding on domestic Sus scrofa domesticus (pigs) and Phacochoerus africanus (warthogs). Infective tsetse may transmit trypanosomes to livestock and humans in the communities studied.
Topics: Animals; Ghana; Tsetse Flies; Cattle; Trypanosomiasis, African; Swine; Trypanosoma; Cross-Sectional Studies; Swine Diseases; Insect Vectors; Forests; Cattle Diseases; Prevalence; Female
PubMed: 38697074
DOI: 10.4269/ajtmh.23-0329