Investigating what makes an African trypanosome human infective

Understanding how a trypanosome becomes human infective.

Most species of trypanosome are unable to infect humans as our blood contains protein complexes, the trypanolytic factors, which cause trypanosome death. The active component within these factors is a pore forming molecule, ApoLI. 

One of the two species of human-infective trypanosomes, Trypanosoma b. rhodesiense, differs from non-infective species due to the presence of a single protein, SRA, which inactivates ApoLI. How does SRA work?

In a collaborative effort with Mark Carrington, we had been trying for a number of years to determine the structure of SRA. Sebastian Zoll was able to find a solution, raising a panel of monoclonal antibodies and finding one which allowed the formation of high quality crystals. Seb also identified the region of SRA which binds to ApoLI. 

This provided the first detailed structural insight into SRA and its mode of interaction with ApoLI. It also showed that prevailing models for how SRA prevents ApoLI function were not compatible with our structural findings. 

However, this study leaves many questions open about how ApoLI works and how it is inactivated by SRA.

Zoll, S., Lane-Serff, H., Mehmood, S., Robinson, C.V., Carrington, M. and Higgins, M.K. (2018) The structure of the serum resistance associated protein of Trypanosoma brucei rhodesiense and its implications for human infectivity. Nature Microbiology 3 295-301