Inducible Natural IgMs Bridge Trypanosome Lytic Factor Assembly and Parasite Recognition

Trypanosomiasis is a devastating neglected tropical disease that affects millions of livestock and thousands of humans each year. Only two subspecies of Trypanosoma brucei can cause disease in humans, while immunity to most trypanosomes is mediated in primates by HDL-associated circulating complexes called trypanosome lytic factors (TLFs) 1 and 2. Both TLFs are similar in composition, though TLF2 uniquely contains non-covalently associated IgM antibodies, the role and origin of which remain unclear. Here, we show that these TLF2-IgMs interact with TLF components and trypanosome surface proteins, including variant surface glycoprotein (VSG), likely facilitating complex biogenesis and TLF uptake into parasites. We also demonstrate that TLF2-IgMs are natural antibodies that, while present at basal concentrations in healthy individuals, are elicited by trypanosome infection in both murine models and human sleeping sickness patients. These data suggest that poly- and selfreactive natural antibodies such as TLF2-IgMs may play a role in antimicrobial immunity.