TY - JOUR
T1 - Beyond immune escape
T2 - a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei
AU - Wiedemar, Natalie
AU - Graf, Fabrice E.
AU - Zwyer, Michaela
AU - Ndomba, Emiliana
AU - Kunz Renggli, Christina
AU - Cal, Monica
AU - Schmidt, Remo S.
AU - Wenzler, Tanja
AU - Mäser, Pascal
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034628812&partnerID=8YFLogxK
U2 - 10.1111/mmi.13854
DO - 10.1111/mmi.13854
M3 - Article
C2 - 28963732
AN - SCOPUS:85034628812
SN - 0950-382X
VL - 107
SP - 57
EP - 67
JO - Molecular Microbiology
JF - Molecular Microbiology
IS - 1
ER -
