How Trypanosoma escaped the immunity

Trypanosoma brucei gambiense
source: Wikipedia, author: Stefan Walkowski

Our immune system protects us from diseases and is thus the number one enemy of all pathogens that try to attack us. However, they are not defenseless either. Evading and manipulating the immune system is their basic ability and Trypanosoma could be considered a master of these techniques. In the early stages of infection, it faces a massive attack of many components of the immune system. Despite that, it managed to develop many elaborate defense mechanisms. Those, that protect the parasite against adaptive immunity, have been described in detail. However, the ones that help it evade innate immunity have been a mystery to an extent.

The complement system is an indispensable part of the innate immunity of host organisms. It consists of around 30 proteins, which are activating in a cascade manner. Three main pathways exist – the classical one, the lectin one, and an alternative one. While the first two are activated by contact with the pathogen and its specific surface structures, the latter can activate spontaneously. It happens mainly in the early stages of infection when the alternative pathway represents a potent first-line defense before an antibody response is mounted. The complement reaction typically results in making a pore in the pathogen cell membrane which thus ruptures and the cell dies. Earlier studies however proved that this is not the case for Trypanosoma brucei gambiense, even though the alternative pathway is activated.

Schematic picture of the three pathways of the complement system – the classical one, the lectin one, and the
alternative one.
source: original paper

The key to this mystery is the invariant surface glycoprotein 65 (ISG65), whose structure in
interaction with parts of the complement system was described in the current study. This
glycoprotein binds the component of the complement system called C3b, thereby preventing the
activation of C5 convertase, which is essential for the formation of the membrane pore deadly to the
parasitic cell. ISG65 also shows high affinity and specificity towards the C3b, which renders the
surface protein very efficient in the scavenging of this component. Thus, it protects the Trypanosoma
against the attacks of alternative pathway of the complement system.

The structure of complexes of ISG65 with C3 and C3b components of the complement system was
resolved using cryogenic electron microscopy (cryo-EM). This technique requires cooling the sample
to a very low temperature, so it retains its structure, and it is possible to study it using an electron
microscope. Cryo-EM is a sort of convenient alternative to X-ray crystallography, which is commonly
used to resolve the structure of molecules because crystalizing a protein can be very challenging.

The structural information about molecules in our body, not only the immune system and its
opponents, are basic building blocks for understanding the function of all organisms. Even though
some light was shed on the interaction of ISG65 of Trypanosoma brucei gambiense with particular
components of our complement system, its exact effect on the C5 convertase remains unclear.
Further research is thus necessary to completely resolve the defense mechanisms of this parasite.

Sülzen, H., Began, J., Dhillon, A. et al. Cryo-EM structures of Trypanosoma brucei gambiense ISG65
with human complement C3 and C3b and their roles in alternative pathway restriction. Nat Commun 14, 2403 (2023).

Magda Křelinová