Epithelial cell invasion by the protozoan parasite Trypanosoma cruzi is enhanced by the presence of an enzyme expressed on its cell surface during the trypomastigote life cycle stage. The enzyme, trans-sialidase, is a member of one of the largest gene families expressed by the parasite and the role of its activity in mediating epithelial cell entry has not hitherto been understood. Here we show that the T. cruzi trans-sialidase generates an eat me signal which is capable of enabling epithelial cell entry. We have utilised purified, recombinant, active (TcTS) and inactive (TcTS2V0) trans-sialidase coated onto beads to challenge an epithelial cell line. We find that trans-sialidase activity acts upon GPCRs present at the epithelial cell synapse with the coated bead, thereby enhancing cell entry. By so doing, we provide evidence that trans-sialidase proteins bind glycans, mediate the formation of distinct synaptic domains and promote macropinocytotic uptake of microparticles into a perinuclear compartment in a manner which may emulate entosis.