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. This, in turn, contributes to the difficulty of generating effective vaccines. In contrast to a classic vaccine approach, our research indicates that IgMs, rather than IgGs, have a protective role during trypanosome infection. Hence, the project focuses on the molecular and cellular mechanisms of IgM based protection, using state-of-the-art methods such as a single cell RNA sequencing, bioinformatics, and proteomics. The final goal is to discover a trypanosome target molecule recognized by protective IgMs. This identified target molecule will be used as an immunogen in a vaccination scheme, skewed to boost generation of protective IgMs against a Trypanosoma brucei challenge.