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T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis

Paul Capewell, Bruno Bucheton, Caroline Clucas, Hamidou Ilboudo, Anneli Cooper, Taylor-Anne Gorman, Kerry O’Neill, Agapitos Patakas, Andrew Platt, Heli Vaikkinen, William Weir, Mamadou Camara, Paul Garside, Vincent Jamonneau, Annette MacLeod
doi: https://doi.org/10.1101/184762
Paul Capewell
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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Bruno Bucheton
5Programme National de Lutte Contre la Trypanosomose Humaine Africaine, Conakry, Guinea
6Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177 INTERTRYP, Campus International de Baillarguet, Montpellier, France
8TrypanoGEN and H3Africa Consortium
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Caroline Clucas
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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Hamidou Ilboudo
5Programme National de Lutte Contre la Trypanosomose Humaine Africaine, Conakry, Guinea
6Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177 INTERTRYP, Campus International de Baillarguet, Montpellier, France
8TrypanoGEN and H3Africa Consortium
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Anneli Cooper
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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Taylor-Anne Gorman
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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Kerry O’Neill
3Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, Graham Kerr Building, University of Glasgow, Glasgow, United Kingdom
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Agapitos Patakas
4Institute of Infection, Immunology and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom
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Andrew Platt
4Institute of Infection, Immunology and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom
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Heli Vaikkinen
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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William Weir
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
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Mamadou Camara
5Programme National de Lutte Contre la Trypanosomose Humaine Africaine, Conakry, Guinea
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Paul Garside
4Institute of Infection, Immunology and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom
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Vincent Jamonneau
6Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177 INTERTRYP, Campus International de Baillarguet, Montpellier, France
7Institut Pierre Richet, Unité de recherche “Trypanosomoses”, Bouaké, Côte d’Ivoire
8TrypanoGEN and H3Africa Consortium
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Annette MacLeod
1Wellcome Trust Centre for a Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Sir Henry Wellcome Building for Comparative Medical Sciences, Glasgow, United Kingdom
8TrypanoGEN and H3Africa Consortium
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Abstract

Infections by many pathogens can result in a wide range of phenotypes, from severe to mild, or even asymptomatic. Understanding the genetic basis of these phenotypes can lead to better tools to treat patients or detect reservoirs. To identify human genetic factors that contribute to symptoms diversity, we examined the range of disease severities caused by the parasite T. b. gambiense, the primary cause of human African trypanosomiasis (HAT). We analyzed the transcriptomes of immune cells from both symptomatic HAT cases and individuals with latent infections. Our analysis identified several genes and pathways that associated with the latent phenotype, primarily suggesting increased T and B cell activation in HAT patients relative to latent infections. We also used these transcriptome data to conduct an exome-wide single nucleotide polymorphism (SNP) association study. This suggested that SNPs in the human major histocompatibility locus (HLA) associate with severity, supporting the transcription data and suggesting that T cell activation is a determining factor in outcome. Finally, to establish if T cell activation controls disease severity, we blocked co-stimulatory dependent T cell activation in an animal model for HAT. This showed that reducing T cell activation during trypanosome infection improves symptoms and reduces parasitemia. Our data has used a combination of transcriptome-wide analysis and an in vivo model to reveal that T cell activation and the HLA locus associate with the development of symptoms during HAT. This may open new avenues for the development of new therapeutics and prognostics.

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Posted September 05, 2017.
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T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis
Paul Capewell, Bruno Bucheton, Caroline Clucas, Hamidou Ilboudo, Anneli Cooper, Taylor-Anne Gorman, Kerry O’Neill, Agapitos Patakas, Andrew Platt, Heli Vaikkinen, William Weir, Mamadou Camara, Paul Garside, Vincent Jamonneau, Annette MacLeod
bioRxiv 184762; doi: https://doi.org/10.1101/184762
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T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis
Paul Capewell, Bruno Bucheton, Caroline Clucas, Hamidou Ilboudo, Anneli Cooper, Taylor-Anne Gorman, Kerry O’Neill, Agapitos Patakas, Andrew Platt, Heli Vaikkinen, William Weir, Mamadou Camara, Paul Garside, Vincent Jamonneau, Annette MacLeod
bioRxiv 184762; doi: https://doi.org/10.1101/184762

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