Trypanosomes and complement: more than one way to die?

African trypanosomes replicate in the blood of mammals, where they must resist destruction by the complement system. Trypanosomes have evolved multiple mechanisms to reduce complement-mediated killing, including a dense cell surface coat, rapid cell surface clearance and receptors (including ISG65) for complement components. Structural and functional studies have revealed how ISG65 binds to complement C3 and its derivatives. Three recent studies propose different mechanisms by which ISG65 might reduce the effects of complement, based on in vitro assays. Uncovering the mechanism of action of ISG65 will require studies of its effect on trypanosome resistance to complement in an infection model. African trypanosomes show a remarkable ability to survive as extracellular parasites in the blood and tissue spaces of an infected mammal. Throughout the infection they are exposed to the molecules and cells of the immune system, including complement. In this opinion piece, we review decades-worth of evidence about how complement affects African trypanosomes. We highlight the discovery of a trypanosome receptor for complement C3 and we critically assess three recent studies which attempt to provide a structural and mechanistic view of how this receptor helps trypanosomes to survive in the presence of complement. [ABSTRACT FROM AUTHOR]