Dr Alex Cook - University of Oxford

Dr Alex Cook

How African trypanosomes evade the complement system: discovery and characterisation of a parasite C3 convertase inhibitor

African trypanosomes replicate within the blood and tissue spaces of their mammalian hosts. As extracellular pathogens, theses parasites are constantly exposed to the complement system: a proteolytic cascade that labels pathogen surfaces as targets for immune attack. To evade adaptive immunity, African trypanosomes perform antigenic variation of highly abundant Variant Surface Glycoprotein on their cell surface. However, the cell surface factors that enable complement escape are poorly understood. 

To address this, we conducted a large-scale screen of a panel of human complement components against a set of putative Trypanosoma brucei surface proteins of unknown function and discovered a novel T. brucei receptor that binds to Complement Factor B. Biochemical 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 extraordinary African trypanosome cell surface has evolved to evade complement-mediated killing.