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Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei

Wiedemar, Natalie and Graf, Fabrice E. and Zwyer, Michaela and Ndomba, Emiliana and Kunz Renggli, Christina and Cal, Monica and Schmidt, Remo S. and Wenzler, Tanja and Mäser, Pascal. (2018) Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei. Molecular Microbiology, 107 (1). pp. 57-67.

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Abstract

Suramin is one of the first drugs developed in a medicinal chemistry program (Bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense. Cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with T. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. Here we show that forward selection for suramin resistance in T. brucei spp. cultures is fast, highly reproducible and linked to antigenic variation. Bloodstream-form trypanosomes are covered by a dense coat of variant surface glycoprotein (VSG), which protects them from their mammalian hosts' immune defenses. Each T. brucei genome contains over 2000 different VSG genes, but only one is expressed at a time. An expression switch to one particular VSG, termed VSGSur , correlated with suramin resistance. Reintroduction of the originally expressed VSG gene in resistant T. brucei restored suramin susceptibility. This is the first report of a link between antigenic variation and drug resistance in African trypanosomes.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wiedemar, Natalie and Zwyer, Michaela and Kunz Renggli, Christina and Cal, Monica and Schmidt, Remo and Wiedemar, Natalie and Zwyer, Michaela and Kunz Renggli, Christina and Cal, Monica and Schmidt, Remo and Wenzler, Tanja and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Blackwell
ISSN:0950-382X
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:14 Sep 2018 14:30
Deposited On:02 Feb 2018 10:33

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