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

摘要

Summary 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 VSG Sur , 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.