Immune factors in snails of the genus Biomphalaria are critical for combating Schistosoma mansoni , the predominant cause of human intestinal schistosomiasis. Independently, many of these factors are known to play an important role in, but not fully define, the compatibility between the model snail B. glabrata , and S. mansoni . Here, we demonstrate association between four, previously characterized humoral immune molecules; Bg FREP3, Bg TEP1, Bg FREP2 and Biomphalysin. We also identify unique immune determinants in the plasma of S. mansoni -resistant B. glabrata that explain the incompatible phenotype. These factors coordinate to initiate haemocyte-mediated deestruction of S. mansoni sporocysts via production of reactive oxygen species. The inclusion of Bg FREP2 in a Bg FREP3-initiated complex that also includes Bg TEP1 almost completely explains resistance to S. mansoni in this model. Our study unifies many independent lines of investigation to provide a more comprehensive understanding of the snail immune system in the context of infection by this important human parasite.

Coordination of humoral immune factors dictates compatibility between Schistosoma mansoni and Biomphalaria glabrata