How do trypanosomes resist killing by the complement system?
Trypanosomes live free in the blood and tissue spaces of infected mammals. They are therefore exposed to mammalian immune defences, including the complement system. This system is centred on the deposition of complement component 3 (C3) on pathogen surfaces, which marks the pathogen, leading to its detection and destruction. Trypanosomes are constantly exposed to the complement system. How do they survive?
A clue came when Olivia MacLeod and Mark Carrington explored the function of a group of trypanosome surface proteins called the invariant surface glycoproteins (ISGs). They found that a family of these, the ISG65s, were receptors for complement C3. Working with Martin Taylor, they then showed that deletion of the ISG65s increased the rate of trypanosome clearance in infected mice. These C3 receptors therefore help trypanosomes to resist the complement system.
Alex was next able to structurally characterise ISG65 and to understand how it binds to a specific region of C3. He found that ISG65 is a curved receptor which wraps around C3. This receptor is linked to the trypanosome surface through a flexible tether, allowing it to move above the thick coat of variant surface glycoproteins which cover the trypanosome surface. This will allow ISG65 to cover C3 molecules which have become attached to the trypanosome surface, masking them and preventing the downstream effects of the complement cascade.
While future studies are required to show exactly how ISG65 blocks the complement pathway, this discovery of trypanosome receptors which have evolved to help the parasite to resist immunity shows us more of the depth of diversity of the remarkable trypanosome surface.
Macleod, O.J.+, Cook, A.D.+, Webb, H., Crow, M., Burns, R., Redpath, M., Seisenberger, S., Trevor, C.E., Peacock, L., Schwede, A., Kimblin, N., Francisco, A.F., Pepperl., Rust, S., Voorheis, P., Gibson, W., Taylor, M.C., Higgins, M.K.* and Carrington, M.* (2022) Invariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor. Nature Communications 13 5085 (+ equal contribution, * joint corresponding)
