Leishmania: fine mapping of the Leishmanolysin molecule's conserved core domains involved in binding and internalization.

The Leishmanolysin molecule's role in the uptake of Leishmania parasites by the human U937 pro-myelocytic cell line was studied, using synthetic peptides representing the complete Leishmania (Viannia) guyanensis Leishmanolysin protein amino acid sequence. The particular peptides present in two protein's core domains efficiently impaired the internalization of promastigotes from four different Leishmania species and modified the kinetics of the binding of heterologous recombinant Leishmanolysin protein. The functional domains which exhibited this property represent a highly conserved portion of the sequence among different Leishmania species. The peptides' inhibitory activity correlated with their ability to bind molecules present on the surface of the human cell line. One of the two functional core domains identified involves the previously described adhesive sequence (SRYD) and the putative zinc-binding motif (HExxH). The second functional core domain includes a third histidine residue coordinated with zinc which determines the molecule's structural features. These findings indicate that the molecular interactions between Leishmanolysin's conserved domains and the macrophage surface molecules efficiently contribute to the parasite's internalization. Induction of neutralizing immune responses, which impair the early parasite-host interaction described here, may be an important alternative in designing synthetic subunit human leishmaniasis vaccines. Copyright 1999 Academic Press.