The primary goal of the original application was to investigate in detail the structure and immunogenicity of oligosaccharides in glycoproteins synthesized by the human blood fluke Schistosoma mansoni. The research has been successful and resulted in the discoveries that the glycosphingolipids in S. mansoni are a new type of structure (designated the """"""""Schisto-core"""""""") and that the Asn-linked oligosaccharides in S. mansoni have two unusual terminal structural motifs, GalNAcbeta1-4- [plus/minusFucalpha1-3)GlcNAcbeta1-2Manalpha1-R (designated terminal GalNAc) and Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-3[Galbeta1-4(Fucalpha1- 3)GlcNAcbeta]n-Manalpha1-R (designated poly-Lewis x or pLex). A set of glycoproteins (designated the 50-100/190 kD pLex glycoproteins) were found to contain the pLex antigen. Antibodies in the sera of infected hamsters were found to react with this pLex structure but not with terminal GalNac. These findings are interesting in light of two related discoveries. First, terminal GalNac structures are found in selected glycoproteins synthesized by mammalian hosts and even other helminthic parasites. Second, a number of carbohydrate binding proteins, termed E- and P-selectins, which are expressed upon inflammation or thrombosis by cells within the human vascular system, bind to Lex-related structures that occur in glycoconjugates on human neutrophils and monocytes. These findings suggest the hypothesis that oligosaccharides in S. mansoni glycoproteins may contribute to interactions of the parasite with host carbohydrate-binding proteins and that these interactions may mitigate the host inflammatory and/or immune responses. To learn more about schistosome glycoconjugates and their possible functions in the infective process 4 specific aims are proposed in this renewal application.
(Aim 1) Characterize and further define the 50-100/190 kD pLex glycoproteins and develop immunological tools for isolating their cDNA and studying their functions.
(Aim 2) Test whether the 50/100/190 kD pLex glycoproteins or some other glycoproteins bind to P- and/or E-selectin or other carbohydrate-binding proteins within the vascular system.
(Aim 3 and 4) Identify the unusual alpha1,3 fucosyltransferase and beta1,4 N- acetylgalactosaminyl-transferase in S. mansoni that synthesize pLex and terminal GalNac structures, respectively, and clone the cDNAs for these enzymes. The long term goals of this research are to gain an understanding at the molecular and biochemical level of the structures of surface glycoconjugates synthesized by S. mansoni and use this information to develop therapeutic and preventive strategies for treatment of this parasitic disease.
