-
Frontiers in Microbiology 2023African trypanosomiasis, a neglected tropical disease, is caused by diverse species of the protozoan parasite belonging to the genus . Although anti-trypanosomal...
African trypanosomiasis, a neglected tropical disease, is caused by diverse species of the protozoan parasite belonging to the genus . Although anti-trypanosomal medications exist, the increase in drug resistance and persistent antigenic variation has necessitated the development of newer and more efficacious therapeutic agents which are selectively toxic to the parasite. In this study, we assessed the trypanocidal efficacy of leaf extract (-extract) . Following treatment of parasites with -extract, we observed a significant decrease in parasite number and an elevation in the expression of the apoptotic markers, Annexin V and 7-Aminoactinomycin D (7AAD). Interestingly, at the same concentration (50 μg/mL), -extract was not cytotoxic to murine whole splenocytes. We also observed a significant increase in pro-inflammatory cytokines and nitric oxide secretion by bone marrow derived macrophages following treatment with (10 μg/mL and 50 μg/mL) compared to PBS treated controls, suggesting that the extract possesses an immune regulatory effect. Treatment of infected mice with -extract led to significant decrease in parasite numbers and a modest increase in mouse survival compared to PBS treated controls. In addition, there was a significant increase in CD4IFN-γ T cells and a decrease in CD4IL-10 T cells in the spleens of infected mice treated with -extract. Interestingly, -extract treatment decreased the activity of superoxide dismutase (an enzyme that protects unicellular organisms from oxidative stress) in parasites but not in splenocytes. Collectively, our study has identified C.f/L-extract as a potential anti-trypanosomal agent that warrant further investigation and possibly explored as a treatment option for infection.
PubMed: 37954253
DOI: 10.3389/fmicb.2023.1275365 -
Journal of Tropical Medicine 2023Human African trypanosomiasis (HAT) and schistosomiasis are neglected parasitic diseases found in the African continent. This study was conducted to determine how...
INTRODUCTION
Human African trypanosomiasis (HAT) and schistosomiasis are neglected parasitic diseases found in the African continent. This study was conducted to determine how primary infection with affects HAT disease progression with a secondary infection with () in a mouse model.
METHODS
Female BALB-c mice (6-8 weeks old) were randomly divided into four groups of 12 mice each. The different groups were infected with (100 cercariae) and (5.0 × 104) separately or together. Twenty-one days after infection with , mice were sacrificed and samples were collected for analysis.
RESULTS
The primary infection with significantly enhanced successive infection by the ; consequently, promoting HAT disease severity and curtailing host survival time. -induced impairment of the neurological integrity and breach of the blood-brain barrier were markedly pronounced on coinfection with Coinfection with and resulted in microcytic hypochromic anemia characterized by the suppression of RBCs, hematocrit, hemoglobin, and red cell indices. Moreover, coinfection of the mice with the two parasites resulted in leukocytosis which was accompanied by the elevation of basophils, neutrophils, lymphocytes, monocytes, and eosinophils. More importantly, coinfection resulted in a significant elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, creatinine, urea, and uric acid, which are the markers of liver and kidney damage. Meanwhile, -driven dyslipidemia was significantly enhanced by the coinfection of mice with Moreover, coinfection with and led to a strong immune response characterized by a significant increase in serum TNF- and IFN-. infection enhanced -induced depletion of cellular-reduced glutathione (GSH) in the brain and liver tissues, indicative of lethal oxidative damage. Similarly, coinfection resulted in a significant rise in nitric oxide (NO) and malondialdehyde (MDA) levels.
CONCLUSION
Primary infection with exacerbates disease severity of secondary infection with in a mouse model that is associated with harmful inflammatory response, oxidative stress, and organ injury.
PubMed: 37954132
DOI: 10.1155/2023/1063169 -
PLoS Neglected Tropical Diseases Nov 2023Animal African trypanosomosis is an important vector-borne disease of livestock in sub-Saharan Africa. Pigs seem relatively tolerant to trypanosome infection and could...
Animal African trypanosomosis is an important vector-borne disease of livestock in sub-Saharan Africa. Pigs seem relatively tolerant to trypanosome infection and could act as a reservoir of trypanosomes affecting animals and humans. Our ability to reliably detect trypanosome infection in pigs depends on the performance of diagnostic tools, which is not well known. In pigs experimentally infected with Trypanosoma brucei brucei, we evaluated the performance of parasitological Buffy Coat Technique (BCT), two molecular (TBR and 5.8S PCR) and four serological tests (CATT, HAT Sero-K-Set rapid diagnostic test-RDT, indirect ELISA, immune trypanolysis). Most diagnostic tests showed high specificity, estimated at 100% (95% CI = 74-100%) with the exception of CATT and RDT whose specificity varied between 100% (95% CI = 74-100%) to 50% (95% CI = 7-93%) during the experiment. The sensitivity of each test fluctuated over the course of the infection. The percentage of positive BCT over the infection (30%) was lower than of positive PCR (56% and 62%, depending on primers). Among the serological tests, the percentage of positive tests was 97%, 96%, 86% and 84% for RDT, ELISA, immune trypanolysis and CATT, respectively. Fair agreement was observed between both molecular tests (κ = 0.36). Among the serological tests, the agreement between the ELISA and the RDT was substantial (κ = 0.65). Our results on the T.b. brucei infection model suggest that serological techniques are efficient in detecting the chronic phase of infection, PCR is able to detect positive samples several months after parasites inoculation while BCT becomes negative. BCT examination and RDT are useful to get a quick information in the field, and BCT can be used for treatment decision. ELISA appears most suited for epidemiological studies. The selection of diagnostic tests for trypanosomosis in pigs depends on the context, the objectives and the available resources.
Topics: Humans; Animals; Swine; Trypanosoma brucei brucei; Trypanosomiasis, African; Trypanosoma; Livestock; Diagnostic Tests, Routine; Sensitivity and Specificity
PubMed: 37943881
DOI: 10.1371/journal.pntd.0011730 -
Journal of Thermal Biology Dec 2023Critical thermal maximum (CT) describes the upper thermal tolerance of an animal where biological functions start to fail. A period of acclimation can enhance CT through... (Meta-Analysis)
Meta-Analysis
Critical thermal maximum (CT) describes the upper thermal tolerance of an animal where biological functions start to fail. A period of acclimation can enhance CT through plasticity, potentially buffering animals from extreme temperatures caused by climate change. Basal and acclimated CT vary within and between species and may be explained by traits related to thermal physiology, such as body size and sex. Differences in CT have not been established among species of tsetse fly (Glossina spp.), vectors of animal and human African trypanosomiasis. Here, we investigated basal CT and its plasticity for five tsetse species following adult acclimation at constant 25 or 30 °C for five days. We then set our findings in context using a meta-analysis on 33 species of Diptera. We find that, of the five tsetse species considered, only Glossina palpalis gambiensis and Glossina brevipalpis exhibited plasticity of CT, with an increase of 0.12 °C and 0.10 °C per 1 °C acclimation respectively. Within some species, higher basal CT values were associated with larger body size and being female, while variation in plasticity (i.e., response to the acclimation temperature) could not be explained by sex or size. Our broader meta-analysis across Diptera revealed overall CT plasticity of 0.06 °C per 1 °C acclimation, versus a similar 0.05 °C mean increase in tsetse. In contrast, there was greater CT plasticity in males compared to females in Diptera. Our study highlights that CT and its plasticity varies even among closely related species. Broader patterns across groups are not always reflected at a finer resolution; we thus emphasise the need for detailed experimental studies across a wide range of insect species to capture their capacity to cope with rapidly warming temperatures.
Topics: Animals; Humans; Male; Female; Glossinidae; Diptera; Acclimatization; Hot Temperature; Temperature
PubMed: 37924664
DOI: 10.1016/j.jtherbio.2023.103745 -
Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
Pathogens (Basel, Switzerland) Oct 2023Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the...
Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the etiological agent), and leishmaniasis (including cutaneous, mucocutaneous, and visceral forms, with multiple species belonging to the genus as etiological agents) are recognized as neglected tropical diseases (NTDs) [...].
PubMed: 37887779
DOI: 10.3390/pathogens12101263 -
Frontiers in Microbiology 2023African animal trypanosomiasis hinders sustainable livestock productivity in sub-Saharan Africa. About 17 million infected cattle are treated with trypanocides annually...
BACKGROUND
African animal trypanosomiasis hinders sustainable livestock productivity in sub-Saharan Africa. About 17 million infected cattle are treated with trypanocides annually but most of the drugs are associated with drawbacks, necessitating the search for a promising chemotherapeutic agent.
OBJECTIVES
In this study, the effects of β-sitosterol on infection were investigated along with its effect on the trans-sialidase gene expressions.
RESULTS
Oral treatment with β-sitosterol at 15 and 30 mg/kg body weight (BW) for 14 days significantly ( < 0.05) reduced parasitemia and ameliorated the parasite-induced anemia. Also, the parasite-induced increase in serum urea level and renal histopathological damage scores in addition to renal hypertrophy was significantly ( < 0.05) reverted following treatment with 30 mg/kg BW β-sitosterol. The compound also significantly ( < 0.05) down-regulated the expression of but not , , and . Correlation analysis between free serum sialic acid with the and gene variants revealed negative correlations in the β-sitosterol-treated groups although they were non-significant ( > 0.05) in the group treated with 15 mg/kg BW β-sitosterol. Similarly, a non-significant negative ( > 0.05) correlation between the biomolecule and the and gene variants was observed in the β-sitosterol-treated groups while positive correlations were observed in the infected untreated control group.
CONCLUSION
The observed effect of β-sitosterol on infection could make the compound a possible template for the design of novel trypanocides.
PubMed: 37886075
DOI: 10.3389/fmicb.2023.1282257 -
BioRxiv : the Preprint Server For... Oct 2023Nitroaromatic drugs are of critical importance for the treatment of trypanosome infections in Africa and the Americas. Fexinidazole recently joined benznidazole and...
Nitroaromatic drugs are of critical importance for the treatment of trypanosome infections in Africa and the Americas. Fexinidazole recently joined benznidazole and nifurtimox in this family when it was approved as the first oral therapy against Human African trypanosomiasis (HAT). Nitroaromatic prodrugs are bioactivated by the trypanosome-specific type I nitroreductase (NTR) enzyme that renders the compounds trypanocidal. A caveat to the specificity of NTR activation is the potential for drug resistance and cross-resistance that can arise if NTR expression or functionality is altered through mutation. The outcomes of NTR bioactivation of nitroaromatic compounds is variable but can include the formation highly reactive open chain nitriles that can damage biomolecules including DNA. A proposed mechanism of action of nitroaromatic compounds is the formation of reactive oxygen species (ROS) resulting in the formation of trypanocidal levels of DNA damage. Fexinidazole made its way to clinical approval without a significant interrogation of its effects on trypanosome biology and a limited understanding of its mechanism of action. Early reports mentioned fexinidazole potentially affects DNA synthesis but without supporting data. In this study, we evaluated and compared the cytotoxic effects of nifurtimox, benznidazole, and fexinidazole on using in vitro analyses. Specifically, we sought to differentiate between the proposed effects of nitroaromatics on DNA damage and DNA synthesis. Toward this goal we generated a novel γH2A-based flow cytometry assay that reports DNA damage formation in conjunction with cell cycle progression. Here we report that fexinidazole's cytotoxic outcomes are distinct from the related drugs nifurtimox and benznidazole. Specifically, we show that fexinidazole treatment results in a pronounced defect in DNA synthesis that reduces the population of parasites in S phase. In contrast, treatment with nifurtimox and benznidazole appear accumulate DNA damage early in cell cycle and result in a defective G population. The findings presented here bring us closer to understanding the anti-trypanosomatid mechanisms of action of nitroaromatic compounds, which will promote improved drug design and help combat potential drug resistance in the future. Our findings also highlight DNA synthesis inhibition as a powerful anti-parasitic drug target.
PubMed: 37873123
DOI: 10.1101/2023.10.09.561529 -
Biology Open Nov 2023Trypanosoma brucei colonise and multiply in the blood vasculature, as well as in various organs of the host's body. Lymph nodes have been previously shown to harbour...
Trypanosoma brucei colonise and multiply in the blood vasculature, as well as in various organs of the host's body. Lymph nodes have been previously shown to harbour large numbers of parasites, and the lymphatic system has been proposed as a key site that allows T. brucei distribution through, and colonization of the mammalian body. However, visualization of host-pathogen interactions in the lymphatic system has never captured dynamic events with high spatial and temporal resolution throughout infection. In our work, we used a mixture of tools including intravital microscopy and ex vivo imaging to study T. brucei distribution in 20 sets of lymph nodes. We demonstrate that lymph node colonization by T. brucei is different across lymph node sets, with the most heavily colonised being the draining lymph nodes of main tissue reservoirs: the gonadal white adipose tissue and pancreas. Moreover, we show that the lymphatic vasculature is a pivotal site for parasite dispersal, and altering this colonization by blocking LYVE-1 is detrimental for parasite survival. Additionally, parasites within the lymphatic vasculature have unique morphological and behavioural characteristics, different to those found in the blood, demonstrating that across both types of vasculature, these environments are physically separated. Finally, we demonstrate that the lymph nodes and the lymphatic vasculature undergo significant alterations during T. brucei infection, resulting in oedema throughout the host's body.
Topics: Animals; Trypanosomiasis, African; Trypanosoma brucei brucei; Lymphatic System; Mammals
PubMed: 37870927
DOI: 10.1242/bio.059992 -
International Journal For Parasitology.... Dec 2023East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major...
East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major problem for cattle farmers in affected regions and there are few methods of control, including a complex infection and treatment vaccine, expensive chemotherapy, and the more widespread tick control through acaricides. New intervention strategies are, therefore, sorely needed. Benzoxaboroles are a versatile class of boron-heterocyclic compounds with demonstrable pharmacological activity against a diverse group of pathogens, including those related to T. parva. In this study, the in vitro efficacy of three benzoxaboroles against the intracellular schizont stage of T. parva was investigated using a flow cytometry approach. Of the benzoxaboroles tested, only one showed any potency, albeit only at high concentrations, even though there is high protein sequence similarity in the CPSF3 protein target compared to other protozoan pathogen species. This finding suggests that benzoxaboroles currently of interest for the treatment of African animal trypanosomiasis, toxoplasmosis, cryptosporidiosis and malaria may not be suitable for the treatment of ECF. We conclude that testing of further benzoxaborole compounds is needed to fully determine whether any lead compounds can be identified to target T. parva.
Topics: Cattle; Animals; Theileria parva; Theileriasis; Cattle Diseases
PubMed: 37866107
DOI: 10.1016/j.ijpddr.2023.10.003