Assessing the fundamental properties of protective IgMs in trypanosomosis, and their mode of action in vaccination.

Salivarian trypanosomes are single-celled extracellular eukaryotic parasites that reside in the blood,
lymphatics, and various tissues. They cause infections in humans, livestock, and game animals.
Trypanosomes thrive in plain sight of the immune system, by deploying multiple evolutionary
acquired evasion strategies, which aim at avoiding antibody-mediated destruction as much as
possible. Interestingly, assessing experimental infections has shown that trypanosomes trigger a
very rapid induction of high-affinity IgGs and other immunoglobulin classes, within the first days of
infection. Hence, it appears as if the induction of Ig class switching, and even accelerated Ig somatic
hypermutation, might be induced as a trypanosome decoy mechanism , to avoid being confronted
with IgMs that have a superior parasite killing capacity. Hence, this project will start (Work package
/ WP1) with the characterization of the protective IgM responses, the mechanism of trypanosome
killing, and cellular IgM sources. As core experimental tool we will use AID-/- mice that are ‘IgMlocked’ and recently have been shown by us to have a much-improved trypanosomosis control. .
Next (WP2 & WP3), AID-/- derived IgMs (including monoclonals) will be used for trypanosome target
antigen identification. Lastly (WP4) an active vaccination approach with these targets will aim at
skewing and boosting the immune response towards generation of protective IgMs against a
Trypanosoma brucei challenge.