Trypanosoma Brucei Gambiense

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Vincent Jamonneau - One of the best experts on this subject based on the ideXlab platform.

  • macrophage migrating inhibitory factor expression is associated with Trypanosoma Brucei Gambiense infection and is controlled by trans acting expression quantitative trait loci in the guinean population
    Infection Genetics and Evolution, 2019
    Co-Authors: Justin Windingoudi Kabore, Anneli Cooper, Paul Capewell, Jacques Kaboré, Vincent Jamonneau, Mamadou Camara, Hamidou Ilboudo, Caroline Clucas, Oumou Camara, Christiane Hertzfowler
    Abstract:

    Infection by Trypanosoma Brucei Gambiense is characterized by a wide array of clinical outcomes, ranging from asymptomatic to acute disease and even spontaneous cure. In this study, we investigated the association between macrophage migrating inhibitory factor (MIF), an important pro-inflammatory cytokine that plays a central role in both innate and acquired immunity, and disease outcome during T. b. Gambiense infection. A comparative expression analysis of patients, individuals with latent infection and controls found that MIF had significantly higher expression in patients (n = 141; 1.25 ± 0.07; p < .0001) and latent infections (n = 25; 1.23 ± 0.13; p = .0005) relative to controls (n = 46; 0.94 ± 0.11). Furthermore, expression decreased significantly after treatment (patients before treatment n = 33; 1.40 ± 0.18 versus patients after treatment n = 33; 0.99 ± 0.10, p = .0001). We conducted a genome wide eQTL analysis on 29 controls, 128 cases and 15 latently infected individuals for whom expression and genotype data were both available. Four loci, including one containing the chemokine CXCL13, were found to associate with MIF expression. Genes at these loci are candidate regulators of increased expression of MIF after infection. Our study is the first data demonstrating that MIF expression is elevated in T. b. Gambiense-infected human hosts but does not appear to contribute to pathology.

  • Trypanosome-induced Interferon-γ production in whole blood stimulation assays is associated with latent Trypanosoma Brucei Gambiense infections
    Microbes and Infection, 2016
    Co-Authors: Hamidou Ilboudo, Jacques Kaboré, Bruno Bucheton, Vincent Jamonneau, Philippe Holzmuller, Mathurin Koffi, Roukiyath Amoussa, André Garcia, David Courtin
    Abstract:

    Control of human African trypanosomiasis (HAT) is highly dependent on the ability to detect and treat infected individuals. However, a number of individuals exposed to Trypanosoma Brucei Gambiense are able to control infection to undetectable levels in blood. They are long-term potential reservoirs and thus a threat for control strategies. Cytokine responses in whole blood stimulation assays were quantified in individuals with contrasting HAT status. Trypanosome-induced IFN-gamma production was only observed in "trypanotolerant" subjects suspected of harboring latent infections. This result contributes new insights into the immune responses associated with infection control and opens novel diagnosis perspectives regarding HAT elimination.

  • Population genetics of Trypanosoma Brucei Gambiense in sleeping sickness patients with treatment failures in the focus of Mbuji-Mayi, Democratic Republic of the Congo.
    Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2014
    Co-Authors: Patient Pati Pyana, Annette Macleod, Philippe Buscher, Nick Van Reet, Modou Séré, Jacques Kaboré, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Vincent Jamonneau
    Abstract:

    Human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) is caused by the protozoan Trypanosoma Brucei Gambiense. Until recently, all patients in the second or neurological stage of the disease were treated with melarsoprol. At the end of the past and the beginning of the present century, alarmingly high relapse rates in patients treated with melarsoprol were reported in isolated HAT foci. In the Mbuji-Mayi focus of DRC, a particular mutation that confers cross resistance for pentamidine and melarsoprol was recently found for all strains studied. Nevertheless, treatment successfully cured a significant proportion of patients. To check for the existence of other possible genetic factors of the parasites, we genotyped trypanosomes isolated from patients before and after treatment (relapsing patients) with eight microsatellite markers. We found no evidence of any genetic correlation between parasite genotype and treatment outcome and we concluded that relapse or cure probably depend more on patients' factors such as disease progression, nutritional or immunological status or co-infections with other pathogens. The existence of a melarsoprol and pentamidine resistance associated mutation at such high rates highlights an increasing problem, even for other drugs, especially those using the same transporters as melarsoprol and pentamidine.

  • a protocol to improve genotyping of problematic microsatellite loci of Trypanosoma Brucei Gambiense from body fluids
    Infection Genetics and Evolution, 2013
    Co-Authors: Jacques Kaboré, Paul Capewell, Annette Macleod, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Mamadou Camara, Hamidou Ilboudo, Vincent Jamonneau
    Abstract:

    Microsatellite genotyping of Trypanosoma Brucei Gambiense, the causative agent of human African trypanosomiasis or sleeping sickness, and population genetics tools, are useful for inferring population parameters such as population size and dispersal. Amplifying parasite DNA directly from body fluids (i.e., blood, lymph or cerebrospinal fluid) allows avoiding costly and tedious isolation phases. It is however associated to increased frequencies of amplification failures (allelic dropouts and/or null alleles) at some loci. In this paper, we present a study focused on three T. Brucei Gambiense microsatellite loci suspected to present amplification problems when amplified from body fluids sampled in Guinean sleeping sickness foci. We checked for the real nature of blank and apparent homozygous genotypes of parasite DNA directly amplified from body fluids and tested the effect of three different DNA quantities of trypanosomes. Our results show that some initially blank and homozygous genotypes happen to be actual heterozygous genotypes. In Guinea, lymph from the cervical nymph nodes, known to contain the highest concentrations of parasites, appeared to provide the best amplification results. Simply repeating the PCR may be enough to retrieve the correct genotype, but we also show that increasing initial DNA content provides better results while undertaking first amplification. We finally propose an optimal protocol for amplifying trypanosome’s DNA directly from body fluids that should be adapted to local characteristics and/or constraints.

  • the mirna and mrna signatures of peripheral blood cells in humans infected with Trypanosoma Brucei Gambiense
    PLOS ONE, 2013
    Co-Authors: Smiths Leong, Jacques Kaboré, Bruno Bucheton, Vincent Jamonneau, Gustave Simo, Mamadou Camara, Hamidou Ilboudo, Jorg D Hoheisel, Christine Clayton
    Abstract:

    Simple, reliable tools for diagnosis of human African Trypanosomiases could ease field surveillance and enhance patient care. In particular, current methods to distinguish patients with (stage II) and without (stage I) brain involvement require samples of cerebrospinal fluid. We describe here an exploratory study to find out whether miRNAs from peripheral blood leukocytes might be useful in diagnosis of human trypanosomiasis, or for determining the stage of the disease. Using microarrays, we measured miRNAs in samples from Trypanosoma Brucei Gambiense-infected patients (9 stage I, 10 stage II), 8 seronegative parasite-negative controls and 12 seropositive, but parasite-negative subjects. 8 miRNAs (out of 1205 tested) showed significantly lower expression in patients than in seronegative, parasite-negative controls, and 1 showed increased expression. There were no clear differences in miRNAs between patients in different disease stages. The miRNA profiles could not distinguish seropositive, but parasitologically negative samples from controls and results within this group did not correlate with those from the trypanolysis test. Some of the regulated miRNAs, or their predicted mRNA targets, were previously reported changed during other infectious diseases or cancer. We conclude that the changes in miRNA profiles of peripheral blood lymphocytes in human African trypanosomiasis are related to immune activation or inflammation, are probably disease-non-specific, and cannot be used to determine the disease stage. The approach has little promise for diagnostics but might yield information about disease pathology.

Philippe Buscher - One of the best experts on this subject based on the ideXlab platform.

  • expression of Trypanosoma Brucei Gambiense antigens in leishmania tarentolae potential for use in rapid serodiagnostic tests rdts
    PLOS Neglected Tropical Diseases, 2015
    Co-Authors: Barrie C Rooney, Philippe Buscher, Stijn Roge, Turid Piening, Mark C Smales
    Abstract:

    The development of rapid serodiagnostic tests for sleeping sickness and other diseases caused by kinetoplastids relies on the affordable production of parasite-specific recombinant antigens. Here, we describe the production of recombinant antigens from Trypanosoma Brucei Gambiense (T.b. Gambiense) in the related species Leishmania tarentolae (L. tarentolae), and compare their diagnostic sensitivity and specificity to native antigens currently used in diagnostic kits against a panel of human sera. A number of T.b. Gambiense protein antigen candidates were chosen for recombinant expression in L. tarentolae based on current diagnostics in field use and recent findings on immunodiagnostic antigens found by proteomic profiling. In particular, the extracellular domains of invariant surface glycoprotein 65 (ISG65), variant surface glycoproteins VSG LiTat 1.3 and VSG LiTat 1.5 were fused with C-terminal histidine tags and expressed as soluble proteins in the medium of cultured, recombinant L. tarentolae. Using affinity chromatography, on average 10 mg/L of recombinant protein was purified from cultures and subsequently tested against a panel of sera from sleeping sickness patients from controls, i.e. persons without sleeping sickness living in HAT endemic countries. The evaluation on sera from 172 T.b. Gambiense human African trypanosomiasis (HAT) patients and from 119 controls showed very high diagnostic potential of the two recombinant VSG and the rISG65 fragments with areas under the curve between 0.97 and 0.98 compared to 0.98 and 0.99 with native VSG LiTat 1.3 and VSG LiTat 1.5 (statistically not different). Evaluation on sera from 78 T.b. rhodesiense HAT patients and from 100 controls showed an acceptable diagnostic potential of rISG65 with an area under the curve of 0.83. These results indicate that a combination of these recombinant antigens has the potential to be used in next generation rapid serodiagnostic tests. In addition, the L. tarentolae expression system enables simple, cheap and efficient production of recombinant kinetoplatid proteins for use in diagnostic, vaccine and drug discovery research that does not rely on animal use to generate materials.

  • Population genetics of Trypanosoma Brucei Gambiense in sleeping sickness patients with treatment failures in the focus of Mbuji-Mayi, Democratic Republic of the Congo.
    Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2014
    Co-Authors: Patient Pati Pyana, Annette Macleod, Philippe Buscher, Nick Van Reet, Modou Séré, Jacques Kaboré, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Vincent Jamonneau
    Abstract:

    Human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) is caused by the protozoan Trypanosoma Brucei Gambiense. Until recently, all patients in the second or neurological stage of the disease were treated with melarsoprol. At the end of the past and the beginning of the present century, alarmingly high relapse rates in patients treated with melarsoprol were reported in isolated HAT foci. In the Mbuji-Mayi focus of DRC, a particular mutation that confers cross resistance for pentamidine and melarsoprol was recently found for all strains studied. Nevertheless, treatment successfully cured a significant proportion of patients. To check for the existence of other possible genetic factors of the parasites, we genotyped trypanosomes isolated from patients before and after treatment (relapsing patients) with eight microsatellite markers. We found no evidence of any genetic correlation between parasite genotype and treatment outcome and we concluded that relapse or cure probably depend more on patients' factors such as disease progression, nutritional or immunological status or co-infections with other pathogens. The existence of a melarsoprol and pentamidine resistance associated mutation at such high rates highlights an increasing problem, even for other drugs, especially those using the same transporters as melarsoprol and pentamidine.

  • a litat 1 5 variant surface glycoprotein derived peptide with diagnostic potential for Trypanosoma Brucei Gambiense
    Tropical Medicine & International Health, 2013
    Co-Authors: Liesbeth Van Nieuwenhove, Philippe Buscher, Fatima Balharbi, Michael Humbert, Yves Guisez, Veerle Lejon
    Abstract:

    objective To evaluate the accuracy of a peptide, corresponding to the variant surface glycoprotein (VSG) LiTat 1.5 amino acid (AA) sequence 268–281 and identified through alignment of monoclonal antibody selected mimotopes, for diagnosis of Trypanosoma Brucei Gambiense sleeping sickness. methods A synthetic biotinylated peptide (peptide 1.5/268–281), native VSG LiTat 1.3 and VSG LiTat 1.5 were tested in an indirect ELISA with 102 sera from patients with HAT and 102 endemic HAT-negative controls. results The area under the curve (AUC) of peptide 1.5/268–281 was 0.954 (95% confidence interval 0.918–0.980), indicating diagnostic potential. The areas under the curve of VSG LiTat 1.3 and LiTat 1.5 were 1.000 (0.982–1.000) and 0.997 (0.973–1.000), respectively, and significantly higher than the AUC of peptide 1.5/268–281. On a model of VSG LiTat 1.5, peptide 1.5/268–281 was mapped near the top of the VSG. conclusions A biotinylated peptide corresponding to AA 268–281 of VSG LiTat 1.5 may replace the native VSG in serodiagnostic tests, but the diagnostic accuracy is lower than for the full-length native VSG LiTat 1.3 and VSG LiTat 1.5.

  • novel markers for treatment outcome in late stage Trypanosoma Brucei Gambiense trypanosomiasis
    Clinical Infectious Diseases, 2008
    Co-Authors: Veerle Lejon, Sylvie Bisser, Francoisxavier Nsiesi, Marleen Boelaert, Isabelle Roger, Dieudonne Mumba Ngoyi, Joris Menten, Jo Robays, Philippe Buscher
    Abstract:

    Background. To date, no biological marker for treatment outcome in human African trypanosomiasis (HAT) has been described. The accuracy of biological markers for prediction of treatment outcome of HAT caused by Trypanosoma Brucei Gambiense was assessed. Methods. Cerebrospinal fluid (CSF) white blood cell (WBC) count and immunoglobulin M (IgM), trypanosome-specific antibody, total protein, and interleukin-10 levels were determined before and up to 24 months after treatment of late-stage HAT. Results. Treatment failure was experienced by 48 of 260 patients. Pretreatment CSF WBC counts 102 cells/ mL, IL-10 concentrations 37 pg/mL, LATEX/IgM end titers 1:32, LATEX/T. b. Gambiense end titers 1:2, and protein concentrations 674 mg/L were associated with treatment failure. Six months after treatment, patients with CSF WBC counts 5 cells/mL were at low risk of HAT recurrence (negative predictive value, 10.93). After 12 months, the combination of CSF WBC count 8 cells/mL and LATEX/IgM end titer 1:4 predicted treatment failure with 97% specificity and 79% sensitivity. Eighteen months after treatment, each marker accurately predicted treatment outcome. The combination of CSF WBC count 8 cells/mL and LATEX/IgM end titer 1:4 was 100% specific for treatment failure after 18 and 24 months. Conclusions. HAT-affected patients with elevated pretreatment CSF levels of WBC, interleukin-10, IgM, trypanosome-specific antibody, and total protein are at risk of treatment failure. Six months after treatment, patients with CSF WBC counts 5 cells/mL can be considered to be cured. The assessment of a combination of CSF WBC count and LATEX/IgM level allowed accurate prediction of outcome beginning at 12 months after treatment, as did each individual marker at 18 months after treatment.

  • equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second stage Trypanosoma Brucei Gambiense sleeping sickness
    The Journal of Infectious Diseases, 2007
    Co-Authors: Sylvie Bisser, Francoisxavier Nsiesi, Veerle Lejon, Pierremarie Preux, Simon Van Nieuwenhove, Constantin Miaka Mia Bilenge, Philippe Buscher
    Abstract:

    BACKGROUND: Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma Brucei Gambiense infection. METHODS: An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment. RESULTS: A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens. CONCLUSION: A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

Veerle Lejon - One of the best experts on this subject based on the ideXlab platform.

  • a litat 1 5 variant surface glycoprotein derived peptide with diagnostic potential for Trypanosoma Brucei Gambiense
    Tropical Medicine & International Health, 2013
    Co-Authors: Liesbeth Van Nieuwenhove, Philippe Buscher, Fatima Balharbi, Michael Humbert, Yves Guisez, Veerle Lejon
    Abstract:

    objective To evaluate the accuracy of a peptide, corresponding to the variant surface glycoprotein (VSG) LiTat 1.5 amino acid (AA) sequence 268–281 and identified through alignment of monoclonal antibody selected mimotopes, for diagnosis of Trypanosoma Brucei Gambiense sleeping sickness. methods A synthetic biotinylated peptide (peptide 1.5/268–281), native VSG LiTat 1.3 and VSG LiTat 1.5 were tested in an indirect ELISA with 102 sera from patients with HAT and 102 endemic HAT-negative controls. results The area under the curve (AUC) of peptide 1.5/268–281 was 0.954 (95% confidence interval 0.918–0.980), indicating diagnostic potential. The areas under the curve of VSG LiTat 1.3 and LiTat 1.5 were 1.000 (0.982–1.000) and 0.997 (0.973–1.000), respectively, and significantly higher than the AUC of peptide 1.5/268–281. On a model of VSG LiTat 1.5, peptide 1.5/268–281 was mapped near the top of the VSG. conclusions A biotinylated peptide corresponding to AA 268–281 of VSG LiTat 1.5 may replace the native VSG in serodiagnostic tests, but the diagnostic accuracy is lower than for the full-length native VSG LiTat 1.3 and VSG LiTat 1.5.

  • Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma Brucei Gambiense sleeping sickness.
    PLoS Neglected Tropical Diseases, 2013
    Co-Authors: Natalia Tiberti, Enock Matovu, Veerle Lejon, Alexandre Hainard, Bertrand Courtioux, John Charles Enyaru, Xavier Robin, Natacha Turck, Krister Kristensson, Dieudonné Mumba Ngoyi
    Abstract:

    BACKGROUND: Post-therapeutic follow-up is essential to confirm cure and to detect early treatment failures in patients affected by sleeping sickness (HAT). Current methods, based on finding of parasites in blood and cerebrospinal fluid (CSF) and counting of white blood cells (WBC) in CSF, are imperfect. New markers for treatment outcome evaluation are needed. We hypothesized that alternative CSF markers, able to diagnose the meningo-encephalitic stage of the disease, could also be useful for the evaluation of treatment outcome. METHODOLOGY/PRINCIPAL FINDINGS: Cerebrospinal fluid from patients affected by Trypanosoma Brucei Gambiense HAT and followed for two years after treatment was investigated. The population comprised stage 2 (S2) patients either cured or experiencing treatment failure during the follow-up. IgM, neopterin, B2MG, MMP-9, ICAM-1, VCAM-1, CXCL10 and CXCL13 were first screened on a small number of HAT patients (n = 97). Neopterin and CXCL13 showed the highest accuracy in discriminating between S2 cured and S2 relapsed patients (AUC 99% and 94%, respectively). When verified on a larger cohort (n = 242), neopterin resulted to be the most efficient predictor of outcome. High levels of this molecule before treatment were already associated with an increased risk of treatment failure. At six months after treatment, neopterin discriminated between cured and relapsed S2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers. CONCLUSIONS/SIGNIFICANCE: In the present study, neopterin was highlighted as a useful marker for the evaluation of the post-therapeutic outcome in patients suffering from sleeping sickness. Detectable levels of this marker in the CSF have the potential to shorten the follow-up for HAT patients to six months after the end of the treatment.

  • Cerebrospinal fluid neopterin as marker of the meningo-encephalitic stage of Trypanosoma Brucei Gambiense sleeping sickness.
    PLoS ONE, 2012
    Co-Authors: Natalia Tiberti, Enock Matovu, Veerle Lejon, Alexandre Hainard, Bertrand Courtioux, John Charles Enyaru, Xavier Robin, Natacha Turck, Krister Kristensson, Dieudonne Mumba Ngoyi
    Abstract:

    BACKGROUND: Sleeping sickness, or human African trypanosomiasis (HAT), is a protozoan disease that affects rural communities in sub-Saharan Africa. Determination of the disease stage, essential for correct treatment, represents a key issue in the management of patients. In the present study we evaluated the potential of CXCL10, CXCL13, ICAM-1, VCAM-1, MMP-9, B2MG, neopterin and IgM to complement current methods for staging Trypanosoma Brucei Gambiense patients. METHODS AND FINDINGS: Five hundred and twelve T. b. Gambiense HAT patients originated from Angola, Chad and the Democratic Republic of the Congo (D.R.C.). Their classification as stage 2 (S2) was based on the number of white blood cells (WBC) (>5/µL) or presence of parasites in the cerebrospinal fluid (CSF). The CSF concentration of the eight markers was first measured on a training cohort encompassing 100 patients (44 S1 and 56 S2). IgM and neopterin were the best in discriminating between the two stages of disease with 86.4% and 84.1% specificity respectively, at 100% sensitivity. When a validation cohort (412 patients) was tested, neopterin (14.3 nmol/L) correctly classified 88% of S1 and S2 patients, confirming its high staging power. On this second cohort, neopterin also predicted both the presence of parasites, and of neurological signs, with the same ability as IgM and WBC, the current reference for staging. CONCLUSIONS: This study has demonstrated that neopterin is an excellent biomarker for staging T. b. Gambiense HAT patients. A rapid diagnostic test for detecting this metabolite in CSF could help in more accurate stage determination.

  • low specificities of hiv diagnostic tests caused by Trypanosoma Brucei Gambiense sleeping sickness
    Journal of Clinical Microbiology, 2010
    Co-Authors: Veerle Lejon, P Buscher, Mumba D Ngoyi, Medard Ilunga, Greet Beelaert, I Maes, Katrien Fransen
    Abstract:

    The accuracy of diagnostic tests for HIV in patients with tropical infections is poorly documented. Human African trypanosomiasis (HAT) is characterized by a polyclonal B-cell activation, constituting a risk for false-positive reactions to diagnostic tests, including HIV tests. A retrospective study of the accuracy of HIV diagnostic tests was performed with 360 human African HAT patients infected with Trypanosoma Brucei Gambiense before treatment and 163 T. b. Gambiense-infected patients 2 years after successful treatment in Mbuji Mayi, East Kasai, Democratic Republic of the Congo. The sensitivities, specificities, and positive predictive values (PPVs) of individual tests and algorithms consisting of 3 rapid tests were determined. The sensitivity of all tests was 100% (11/11). The low specificity (96.3%, 335/348) and PPV (45.8%, 11/24) of a classical seroconfirmation strategy (Vironostika enzyme-linked immunosorbent assay [ELISA] followed by line immunoassay) complicated the determination of HIV status, which had to be determined by PCR. The specificities of the rapid diagnostic tests were 39.1% for Determine (136/348); 85.3 to 92.8% (297/348 to 323/348) for Vikia, ImmunoFlow, DoubleCheck, and Bioline; and 96.6 to 98.3% (336/348 to 342/348) for Uni-Gold, OraQuick, and Stat-Pak. The specificity of Vironostika was 67.5% (235/348). PPVs ranged between 4.9 and 64.7%. Combining 3 different rapid tests resulted in specificities of 98.3 to 100% (342/348 to 348/348) and PPVs of 64.7 to 100% (11/17 to 11/11). For cured HAT patients, specificities were significantly higher for Vironostika, Determine, Uni-Gold, and ImmunoFlow. T. b. Gambiense infection decreases the specificities of antibody detection tests for HIV diagnosis. Unless tests have been validated for interference with HAT, HIV diagnosis using classical algorithms in untreated HAT patients should be avoided. Specific, validated combinations of 3 HIV rapid tests can increase specificity.

  • novel markers for treatment outcome in late stage Trypanosoma Brucei Gambiense trypanosomiasis
    Clinical Infectious Diseases, 2008
    Co-Authors: Veerle Lejon, Sylvie Bisser, Francoisxavier Nsiesi, Marleen Boelaert, Isabelle Roger, Dieudonne Mumba Ngoyi, Joris Menten, Jo Robays, Philippe Buscher
    Abstract:

    Background. To date, no biological marker for treatment outcome in human African trypanosomiasis (HAT) has been described. The accuracy of biological markers for prediction of treatment outcome of HAT caused by Trypanosoma Brucei Gambiense was assessed. Methods. Cerebrospinal fluid (CSF) white blood cell (WBC) count and immunoglobulin M (IgM), trypanosome-specific antibody, total protein, and interleukin-10 levels were determined before and up to 24 months after treatment of late-stage HAT. Results. Treatment failure was experienced by 48 of 260 patients. Pretreatment CSF WBC counts 102 cells/ mL, IL-10 concentrations 37 pg/mL, LATEX/IgM end titers 1:32, LATEX/T. b. Gambiense end titers 1:2, and protein concentrations 674 mg/L were associated with treatment failure. Six months after treatment, patients with CSF WBC counts 5 cells/mL were at low risk of HAT recurrence (negative predictive value, 10.93). After 12 months, the combination of CSF WBC count 8 cells/mL and LATEX/IgM end titer 1:4 predicted treatment failure with 97% specificity and 79% sensitivity. Eighteen months after treatment, each marker accurately predicted treatment outcome. The combination of CSF WBC count 8 cells/mL and LATEX/IgM end titer 1:4 was 100% specific for treatment failure after 18 and 24 months. Conclusions. HAT-affected patients with elevated pretreatment CSF levels of WBC, interleukin-10, IgM, trypanosome-specific antibody, and total protein are at risk of treatment failure. Six months after treatment, patients with CSF WBC counts 5 cells/mL can be considered to be cured. The assessment of a combination of CSF WBC count and LATEX/IgM level allowed accurate prediction of outcome beginning at 12 months after treatment, as did each individual marker at 18 months after treatment.

Annette Macleod - One of the best experts on this subject based on the ideXlab platform.

  • Population genetics of Trypanosoma Brucei Gambiense in sleeping sickness patients with treatment failures in the focus of Mbuji-Mayi, Democratic Republic of the Congo.
    Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2014
    Co-Authors: Patient Pati Pyana, Annette Macleod, Philippe Buscher, Nick Van Reet, Modou Séré, Jacques Kaboré, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Vincent Jamonneau
    Abstract:

    Human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) is caused by the protozoan Trypanosoma Brucei Gambiense. Until recently, all patients in the second or neurological stage of the disease were treated with melarsoprol. At the end of the past and the beginning of the present century, alarmingly high relapse rates in patients treated with melarsoprol were reported in isolated HAT foci. In the Mbuji-Mayi focus of DRC, a particular mutation that confers cross resistance for pentamidine and melarsoprol was recently found for all strains studied. Nevertheless, treatment successfully cured a significant proportion of patients. To check for the existence of other possible genetic factors of the parasites, we genotyped trypanosomes isolated from patients before and after treatment (relapsing patients) with eight microsatellite markers. We found no evidence of any genetic correlation between parasite genotype and treatment outcome and we concluded that relapse or cure probably depend more on patients' factors such as disease progression, nutritional or immunological status or co-infections with other pathogens. The existence of a melarsoprol and pentamidine resistance associated mutation at such high rates highlights an increasing problem, even for other drugs, especially those using the same transporters as melarsoprol and pentamidine.

  • a protocol to improve genotyping of problematic microsatellite loci of Trypanosoma Brucei Gambiense from body fluids
    Infection Genetics and Evolution, 2013
    Co-Authors: Jacques Kaboré, Paul Capewell, Annette Macleod, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Mamadou Camara, Hamidou Ilboudo, Vincent Jamonneau
    Abstract:

    Microsatellite genotyping of Trypanosoma Brucei Gambiense, the causative agent of human African trypanosomiasis or sleeping sickness, and population genetics tools, are useful for inferring population parameters such as population size and dispersal. Amplifying parasite DNA directly from body fluids (i.e., blood, lymph or cerebrospinal fluid) allows avoiding costly and tedious isolation phases. It is however associated to increased frequencies of amplification failures (allelic dropouts and/or null alleles) at some loci. In this paper, we present a study focused on three T. Brucei Gambiense microsatellite loci suspected to present amplification problems when amplified from body fluids sampled in Guinean sleeping sickness foci. We checked for the real nature of blank and apparent homozygous genotypes of parasite DNA directly amplified from body fluids and tested the effect of three different DNA quantities of trypanosomes. Our results show that some initially blank and homozygous genotypes happen to be actual heterozygous genotypes. In Guinea, lymph from the cervical nymph nodes, known to contain the highest concentrations of parasites, appeared to provide the best amplification results. Simply repeating the PCR may be enough to retrieve the correct genotype, but we also show that increasing initial DNA content provides better results while undertaking first amplification. We finally propose an optimal protocol for amplifying trypanosome’s DNA directly from body fluids that should be adapted to local characteristics and/or constraints.

  • the tgsgp gene is essential for resistance to human serum in Trypanosoma Brucei Gambiense
    PLOS Pathogens, 2013
    Co-Authors: Paul Capewell, Rudo Kieft, Anneli Cooper, Stephen L Hajduk, Nicola Veitch, Caroline Clucas, Eric Dejesus, Pieter C Steketee, William Weir, Annette Macleod
    Abstract:

    Trypanosoma Brucei Gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. Brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. Gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. Gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. Gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. Gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. Gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. Gambiense.

  • human host determinants influencing the outcome of Trypanosoma Brucei Gambiense infections
    Parasite Immunology, 2011
    Co-Authors: Bruno Bucheton, Annette Macleod, Vincent Jamonneau
    Abstract:

    Since first identified, human African trypanosomiasis (HAT) or sleeping sickness has been described as invariably fatal. Increasing data however argue that infection by Trypanosoma Brucei Gambiense, the causative agent of HAT, results in a wide range of outcomes in its human host and importantly that a number of subjects in endemic areas are apparently able to control infection to low levels, undetectable by the classical parasitological tests used in the field. Thus, trypanotolerance seems to occur in humans as has already been described in cattle or in the rodent experimental models of infection. This review focuses on the description of the diversity of outcomes resulting from T. b. Gambiense in humans and on the host factors involved. The consequences/impacts on HAT epidemiology resulting from this diversity are also discussed with regard to implementing sustainable HAT control strategies.

  • first evidence that parasite infecting apparent aparasitemic serological suspects in human african trypanosomiasis are Trypanosoma Brucei Gambiense and are similar to those found in patients
    Infection Genetics and Evolution, 2011
    Co-Authors: Jacques Kaboré, Annette Macleod, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Mamadou Camara, Hamidou Ilboudo, Mathurin Koffi, Craig W Duffy, Vincent Jamonneau
    Abstract:

    Thanks to its sensitivity and its ease of use in the field, the card agglutination test for trypanosomiasis (CATT) is widely used for serological screening of Trypanosoma Brucei Gambiense human African trypanosomiasis (HAT). Positive subjects are then examined by microscopy to confirm the disease. However, the CATT exhibits false-positive results raising the question of whether CATT-positive subjects who are not confirmed by microscopic detection of trypanosomes (SERO) are truly exposed to T.b. Gambiense infection. For this purpose, we applied microsatellite genotyping on DNA extracted from blood of both HAT confirmed patients and SERO subjects in Guinea and Cote d'Ivoire since microsatellite genotyping has proved useful for the study of T.b. Gambiense genetic diversity. Problems of amplification failures raise the question of the sensitivity of microsatellite markers when applied on biological samples especially from SERO subjects for who low blood parasitaemia are suspected. Nevertheless, we have shown that the trypanosomes from SERO individuals that have been genotyped belong to T.b. Gambiense group 1 and were identical to those found in HAT patients. These results constitute the first evidences that at least some SERO are indeed infected by T.b. Gambiense group 1 and that they may constitute a human reservoir of parasite in HAT foci. Whether these individuals should undergo treatment remains an open question as long as their role in HAT transmission is unknown. Our results strongly recommend the follow-up of such subjects to improve control strategies.

Jacques Kaboré - One of the best experts on this subject based on the ideXlab platform.

  • macrophage migrating inhibitory factor expression is associated with Trypanosoma Brucei Gambiense infection and is controlled by trans acting expression quantitative trait loci in the guinean population
    Infection Genetics and Evolution, 2019
    Co-Authors: Justin Windingoudi Kabore, Anneli Cooper, Paul Capewell, Jacques Kaboré, Vincent Jamonneau, Mamadou Camara, Hamidou Ilboudo, Caroline Clucas, Oumou Camara, Christiane Hertzfowler
    Abstract:

    Infection by Trypanosoma Brucei Gambiense is characterized by a wide array of clinical outcomes, ranging from asymptomatic to acute disease and even spontaneous cure. In this study, we investigated the association between macrophage migrating inhibitory factor (MIF), an important pro-inflammatory cytokine that plays a central role in both innate and acquired immunity, and disease outcome during T. b. Gambiense infection. A comparative expression analysis of patients, individuals with latent infection and controls found that MIF had significantly higher expression in patients (n = 141; 1.25 ± 0.07; p < .0001) and latent infections (n = 25; 1.23 ± 0.13; p = .0005) relative to controls (n = 46; 0.94 ± 0.11). Furthermore, expression decreased significantly after treatment (patients before treatment n = 33; 1.40 ± 0.18 versus patients after treatment n = 33; 0.99 ± 0.10, p = .0001). We conducted a genome wide eQTL analysis on 29 controls, 128 cases and 15 latently infected individuals for whom expression and genotype data were both available. Four loci, including one containing the chemokine CXCL13, were found to associate with MIF expression. Genes at these loci are candidate regulators of increased expression of MIF after infection. Our study is the first data demonstrating that MIF expression is elevated in T. b. Gambiense-infected human hosts but does not appear to contribute to pathology.

  • differences in pathogenicity and virulence of Trypanosoma Brucei Gambiense field isolates in experimentally infected balb c mice
    Infection Genetics and Evolution, 2018
    Co-Authors: Jacques Kaboré, Thierry De Meeûs, Mamadou Camara, Hamidou Ilboudo, Mathurin Koffi, Sophie Ravel, Oumou Camara, Djeneba Sanou, Hassane Sakande, Adrien Marie Gaston Belem
    Abstract:

    Trypanosoma Brucei Gambiense (T. b. Gambiense) is the major causative agent of human African trypanosomiasis (HAT). A great variety of clinical outcomes have been observed in West African foci, probably due to complex host-parasite interactions. In order to separate the roles of parasite genetic diversity and host variability, we have chosen to precisely characterize the pathogenicity and virulence of T. b. Gambiense field isolates in a mouse model. Thirteen T. b. Gambiense strains were studied in experimental infections, with 20 Balb/C infected mice per isolate. Mice were monitored for 30 days, in which mortality, parasitemia, anemia, and weight were recorded. Mortality rate, prepatent period, and maximum parasitemia were estimated, and a survival analysis was performed to compare strain pathogenicity. Mixed models were used to assess parasitemia dynamics, weight, and changes in Packed Cell Volume (PCV). Finally, a multivariate analysis was performed to infer relationships between all variables. A large phenotypic diversity was observed. Pathogenicity was highly variable, ranging from strains that kill their host within 9 days to a non-pathogenic strain (no deaths during the experiment). Virulence was also variable, with maximum parasitemia values ranging from 42 million to 1 billion trypanosomes/ml. Reduced PCV and weight occurred in the first two weeks of the infection, with the exception of two strains. Finally, the global analysis highlighted three groups of strains: a first group with highly pathogenic strains showing an early mortality associated with a short prepatent period; a second group of highly virulent strains with intermediate pathogenicity; and a third group of isolates characterized by low pathogenicity and virulence patterns. Such biological differences could be related to the observed clinical diversity in HAT. A better understanding of the biological pathways underlying the observed phenotypic diversity could thus help to clarify the complex nature of the host-parasite interactions that determine the resistance/susceptibility status to T. Brucei Gambiense.

  • Trypanosome-induced Interferon-γ production in whole blood stimulation assays is associated with latent Trypanosoma Brucei Gambiense infections
    Microbes and Infection, 2016
    Co-Authors: Hamidou Ilboudo, Jacques Kaboré, Bruno Bucheton, Vincent Jamonneau, Philippe Holzmuller, Mathurin Koffi, Roukiyath Amoussa, André Garcia, David Courtin
    Abstract:

    Control of human African trypanosomiasis (HAT) is highly dependent on the ability to detect and treat infected individuals. However, a number of individuals exposed to Trypanosoma Brucei Gambiense are able to control infection to undetectable levels in blood. They are long-term potential reservoirs and thus a threat for control strategies. Cytokine responses in whole blood stimulation assays were quantified in individuals with contrasting HAT status. Trypanosome-induced IFN-gamma production was only observed in "trypanotolerant" subjects suspected of harboring latent infections. This result contributes new insights into the immune responses associated with infection control and opens novel diagnosis perspectives regarding HAT elimination.

  • Population genetics of Trypanosoma Brucei Gambiense in sleeping sickness patients with treatment failures in the focus of Mbuji-Mayi, Democratic Republic of the Congo.
    Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2014
    Co-Authors: Patient Pati Pyana, Annette Macleod, Philippe Buscher, Nick Van Reet, Modou Séré, Jacques Kaboré, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Vincent Jamonneau
    Abstract:

    Human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) is caused by the protozoan Trypanosoma Brucei Gambiense. Until recently, all patients in the second or neurological stage of the disease were treated with melarsoprol. At the end of the past and the beginning of the present century, alarmingly high relapse rates in patients treated with melarsoprol were reported in isolated HAT foci. In the Mbuji-Mayi focus of DRC, a particular mutation that confers cross resistance for pentamidine and melarsoprol was recently found for all strains studied. Nevertheless, treatment successfully cured a significant proportion of patients. To check for the existence of other possible genetic factors of the parasites, we genotyped trypanosomes isolated from patients before and after treatment (relapsing patients) with eight microsatellite markers. We found no evidence of any genetic correlation between parasite genotype and treatment outcome and we concluded that relapse or cure probably depend more on patients' factors such as disease progression, nutritional or immunological status or co-infections with other pathogens. The existence of a melarsoprol and pentamidine resistance associated mutation at such high rates highlights an increasing problem, even for other drugs, especially those using the same transporters as melarsoprol and pentamidine.

  • a protocol to improve genotyping of problematic microsatellite loci of Trypanosoma Brucei Gambiense from body fluids
    Infection Genetics and Evolution, 2013
    Co-Authors: Jacques Kaboré, Paul Capewell, Annette Macleod, Thierry De Meeûs, Bruno Bucheton, Adrien Marie Gaston Belem, Mamadou Camara, Hamidou Ilboudo, Vincent Jamonneau
    Abstract:

    Microsatellite genotyping of Trypanosoma Brucei Gambiense, the causative agent of human African trypanosomiasis or sleeping sickness, and population genetics tools, are useful for inferring population parameters such as population size and dispersal. Amplifying parasite DNA directly from body fluids (i.e., blood, lymph or cerebrospinal fluid) allows avoiding costly and tedious isolation phases. It is however associated to increased frequencies of amplification failures (allelic dropouts and/or null alleles) at some loci. In this paper, we present a study focused on three T. Brucei Gambiense microsatellite loci suspected to present amplification problems when amplified from body fluids sampled in Guinean sleeping sickness foci. We checked for the real nature of blank and apparent homozygous genotypes of parasite DNA directly amplified from body fluids and tested the effect of three different DNA quantities of trypanosomes. Our results show that some initially blank and homozygous genotypes happen to be actual heterozygous genotypes. In Guinea, lymph from the cervical nymph nodes, known to contain the highest concentrations of parasites, appeared to provide the best amplification results. Simply repeating the PCR may be enough to retrieve the correct genotype, but we also show that increasing initial DNA content provides better results while undertaking first amplification. We finally propose an optimal protocol for amplifying trypanosome’s DNA directly from body fluids that should be adapted to local characteristics and/or constraints.

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