Authors

A Cook¹; O Macleod²; M Crow²; H Webb²; R Burns²; M Redpath²; S Seisenberger²; C Trevor²; L Peacock⁴; A Schwede²; N Kimblin²; AF Francisco⁶; J Pepperl²; S Rust⁵; P Voorheis³; W Gibson⁴; MC Taylor⁶; M Higgins¹; M Carrington²;  ¹ University of Oxford, Department of Biochemistry, UK;  ² University of Cambridge, Department of Biochemistry, UK;  ³ Trinity College Dublin, Ireland;  ⁴ School of Biological Sciences & Bristol Veterinary School, University of Bristol, UK;  ⁵ AstraZeneca, UK;  ⁶ Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, UK

Discussion

African Trypanosomes replicate in the blood of mammalian hosts yet are completely exposed to the adaptive and innate immune systems. Despite this, Trypanosomes can sustain long-term infections - how can this parasite survive constant host immune-surveillance? Trypanosomes evade the adaptive immune response through antigenic variation of a surface coat consisting of a dense layer of variable surface glycoprotein. However, very little is known about how they negate the innate system, including the blood circulating complement system. We have discovered that an invariant surface glycoprotein, ISG65, is a receptor for Complement Component 3 (C3). We show how ISG65 binds to the thioester domain of C3b. We also show that knockout of the ISG65 locus greatly decreases the pathogenicity of trypanosomes in a mouse model. Deposition of C3b on pathogen surfaces is a central point in activation of the complement system and C3b has been observed on trypanosome surfaces. Our findings therefore suggest that trypanosomes have a C3 receptor distributed across their surfaces that greatly decreases their susceptibility to complement-mediated killing.