An African trypanosome surface protein inhibits amplification of the complement system

Abstract

African trypanosomes replicate within the blood and tissue spaces of their mammalian hosts. As extracellular pathogens, they are constantly exposed to immune cells and molecules and are susceptible to killing by components of the complement system. In this study, we conducted a large-scale screen of a panel of human complement components against a set of putative T. brucei surface proteins and discovered a novel T. brucei receptor that binds to complement Factor B. Biochemical and structural characterisation of this protein revealed it to be a potent inhibitor of the C3bBb convertase, a central enzyme in amplification of the complement cascade. Structural studies show that this C3bBb receptor bridges C3b and Bb in a conformation which is incompatible with its catalytic activity, directly blocking C3bBb convertase function. This reveals a novel mechanism of C3bBb convertase regulation and deepens insight into how the African trypanosome cell surface has evolved to evade complement-mediated killing.