A5008610496- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Synthesis and Biological Evaluation
- Biochemical and Molecular Research
- Parasites and Host Interactions
- Synthesis and biological activity
- Organic Chemistry Cycloaddition Reactions
- Parasitic Diseases Research and Treatment
- Insect symbiosis and bacterial influences
- Monoclonal and Polyclonal Antibodies Research
- HIV/AIDS drug development and treatment
- Malaria Research and Control
- Eicosanoids and Hypertension Pharmacology
- Mosquito-borne diseases and control
- Helminth infection and control
- Bioactive Compounds and Antitumor Agents
- Calcium signaling and nucleotide metabolism
- Immune Cell Function and Interaction
- Plant Virus Research Studies
- Cultural and Social Studies in Latin America
- Chromosomal and Genetic Variations
- Parasitic Infections and Diagnostics
- CRISPR and Genetic Engineering
- Synthesis of β-Lactam Compounds
- Chemical Synthesis and Reactions
University of Southampton
2018-2025
University of London
2015-2024
London School of Hygiene & Tropical Medicine
2015-2024
Centre for Cancer Biology
2022
West London Mental Health NHS Trust
2016-2019
Southampton General Hospital
2018
The Netherlands Cancer Institute
1994-1998
Sorbonne Université
1998
University of Bristol
1998
Oncode Institute
1994-1998
Nifurtimox and benznidazole are the front-line drugs used to treat Chagas disease, most important parasitic infection in Americas. These agents function as prodrugs must be activated within parasite have trypanocidal effects. Despite >40 years of research, mechanism(s) action resistance remained elusive. Here, we report that trypanosomes, both by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), down-regulation this explains how may emerge. Loss...
Chronic Trypanosoma cruzi infections lead to cardiomyopathy in 20-30% of cases.A causal link between cardiac infection and pathology has been difficult establish because a lack robust methods detect scarce, focally distributed parasites within tissues.We developed highly sensitive bioluminescence imaging system based on T. expressing novel luciferase that emits tissue-penetrating orange-red light.This enabled long-term serial evaluation parasite burdens individual mice with an vivo limit...
Benznidazole is the frontline drug used against Trypanosoma cruzi, causative agent of Chagas disease. However, treatment failures are often reported. Here, we demonstrate that independently acquired mutations in gene encoding a mitochondrial nitroreductase (TcNTR) can give rise to distinct drug-resistant clones within single population. Following selection benznidazole-resistant parasites, all examined had lost one chromosomes containing TcNTR gene. Sequence analysis remaining allele...
ABSTRACT The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and experimental murine models. Despite this, a recent clinical trial it displayed limited curative potential. Drug testing is problematic Chagas disease because of difficulties demonstrating sterile cure, particularly during the chronic stage infection when parasite burden extremely low tissue distribution ill defined. To better assess efficacy acute disease, we have exploited highly...
Benznidazole is the main drug used to treat Trypanosoma cruzi infections. However, frequent instances of treatment failure have been reported. To better understand potential resistance mechanisms, we analysed three clones isolated from a single parasite population that had undergone benznidazole-selection. These exhibited differing levels benznidazole-resistance (varying between 9 and 26-fold), displayed cross-resistance nifurtimox (2 4-fold). Each clone acquired stop-codon-generating...
Host and parasite diversity are suspected to be key factors in Chagas disease pathogenesis. Experimental investigation of underlying mechanisms is hampered by a lack tools detect scarce, pleiotropic infection foci. We developed sensitive imaging models track Trypanosoma cruzi dynamics quantify tissue-specific loads, with minimal sampling bias. used this technology investigate cardiomyopathy caused highly divergent strains BALB/c, C3H/HeN C57BL/6 mice. The gastrointestinal tract was...
Background Infection with Trypanosoma cruzi causes Chagas disease, a major public health problem throughout Latin America. There is no vaccine and the only drugs have severe side effects. Efforts to generate new therapies are hampered by limitations in our understanding of parasite biology disease pathogenesis. Studies compromised complexity long-term nature infection, fact that parasites barely detectable during chronic stage. In addition, functional dissection T. has been restricted...
Trypanosoma cruzi glutathione-dependent peroxidase I (TcGPXI) can reduce fatty acid, phospholipid, and short chain organic hydroperoxides utilizing a novel redox cycle in which enzyme activity is linked to the reduction of trypanothione, parasite-specific thiol, by glutathione. Here we show that TcGPXI also be trypanothione an alternative pathway involving thioredoxin-like protein tryparedoxin. The presence this new was first detected using dialyzed soluble fractions parasite extract....
Trypanosoma cruzi undergo PCD (programmed cell death) under appropriate stimuli, the mechanisms of which remain to be established. In present study, we show that stimulation in T. epimastigotes by FHS (fresh human serum) results rapid (<1 h) externalization phosphatidylserine and depletion low molecular mass thiols dihydrotrypanothione glutathione. Concomitantly, enhanced generation oxidants was established EPR immuno-spin trapping radicals using DMPO (5,5-dimethylpyrroline-N-oxide)...
Trypanosoma cruzi causes Chagas disease, the most important parasitic infection in Latin America. Major pathologies include severe damage to heart and digestive tract, although symptoms do not usually appear until decades after infection. Research has been hampered by complex nature of disease technical difficulties locating extremely low number parasites. Here, using highly sensitive imaging technology, we reveal sites parasite persistence during chronic-stage infections experimental mice...
The unusual DNA base β- d -glucosyl-hydroxymethyluracil, called “J,” replaces ≈0.5–1% of Thy in African trypanosomes but has not been found other organisms thus far. In Trypanosoma brucei , J is located predominantly repetitive DNA, and its presence correlates with the silencing telomeric genes. Using antibodies specific for J, we have developed sensitive assays to screen a range that limited undergo antigenic variation conserved among Kinetoplastida. all kinetoplastids tested, including...
Until recently, it had been thought that trypanosomes lack glutathione peroxidase activity. Here we report the subcellular localization and biochemical properties of a second glutathione-dependent from Trypanosoma cruzi (TcGPXII). TcGPXII is single-copy gene which encodes 16kDa protein appears to be specifically dependent on as source reducing equivalents. Recombinant was purified shown have activity towards narrow substrate range, restricted hydroperoxides fatty acids phospholipids....
Background Human African trypanosomiasis is caused by infection with parasites of the Trypanosoma brucei species complex, and threatens over 70 million people in sub-Saharan Africa. Development new drugs hampered limitations current rodent models, particularly for stage II infections, which occur once have accessed CNS. Bioluminescence imaging pathogens expressing firefly luciferase (emission maximum 562 nm) has been adopted a number vivo models disease to monitor dissemination,...
Human African trypanosomiasis (HAT) manifests in two stages of disease: firstly, haemolymphatic, and secondly, an encephalitic phase involving the central nervous system (CNS). New drugs to treat second-stage disease are urgently needed, yet testing novel drug candidates is a slow process because established animal model relies on detecting parasitemia blood as late 180 days after treatment. To expedite compound screening, we have modified GVR35 strain Trypanosoma brucei express luciferase,...
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, cruzi Leishmania species, among most deadly neglected tropical diseases. The development of drugs that active against several is appealing from a clinical economic viewpoint, seems feasible, as these parasites share metabolic pathways hence might be treatable common drugs. From benzonapthyridine 1, an inhibitor acetylcholinesterase (AChE) for we have found...
Abstract Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi . Transmission cycles are maintained haematophagous triatomine bug vectors that carry infective T. in their faeces. Most human infections acquired contamination of mucosal membranes with faeces after being bitten, however, can be transmitted several other routes. Oral transmission an increasingly important aspect epidemiology, typically involving food or drink products contaminated triatomines. This has...
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5-8 million people in Latin America. Although nitroheterocyclic compound benznidazole has been front-line drug for several decades, treatment failures are common. Benznidazole a pro-drug bio-activated within mitochondrial nitroreductase TcNTR-1, leading to generation of reactive metabolites that have trypanocidal activity. To better assess action resistance, we sequenced genomes T. Y strain (35.5 Mb) three...
Background Despite extensive clinical use, the mechanisms that lead to therapeutic resistance anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought determine how interactions between Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect activity these are impacted by immune environment. Methods Mouse human with different binding profiles were generated characterized in vitro. The ability elicit T-cell responses vivo was first assessed a...