How do trypanosomes evade destruction by binding factor H?

Pretending to be human – finding a factor H receptor on the trypanosome surface

This study started when Olivia Macleod, working with Mark Carrington, began the search for novel receptors for human serum molecules in the African trypanosome. The genome of this parasite contains a set of proteins which appear very similar in structure to the haptoglobin-haemoglobin receptor. Are they also receptor proteins? And if so, what do they bind?

Olivia found that one of these receptors, known as 4020, bound to the factor H molecule in human serum. Factor H is part of the human complement system. Complement molecules are part of our defences against pathogens and the accumulation of these molecules onto the surfaces of bacteria and parasites helps the body to destroy them. Factor H is a negative regulator of complement and so Olivia reasoned that the trypanosomes might be borrowing it from human serum to prevent them from being destroyed by the complement system.

We next determined the structure of the factor H receptor bound to a domain from factor H. This showed that the receptor holds factor H in such a way that it will still be able to bind to complement, allowing it to prevent complement activation and parasite destruction.

Olivia was also able to show that parasites which lack the factor H receptor can still grow in human blood. However, they do struggle to grow within a tsetse fly. This was initially surprising. However, trypanosomes within the gut of the tsetse fly are exposed to complement as the fly feeds on human blood. It seems as though trypanosomes are susceptible to being killed by complement while in the fly and that this receptor helps them to survive.

The factor H receptor is therefore important for successful transmission of trypanosomes from human to tsetse fly, and therefore back to human, helping the parasite to pass through its life cycle and cause further disease.

Macleod, O.J.S., Bart, J., MacGregor, P., Peacock, L., Savill, N.J., Hester, S., Ravel, S., Sunter, J.D., Trevor, C., Rust, S., Vaughan, T.J., Minter, R., Mohammed, S., Gibson, W., Taylor, M.C., Higgins, M.K.* and Carrington, M.* (2020) A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies. Nature Communicantions 11, 1326