Dissecting the paracoccin interaction with toll-like receptors N-glycans: a necessary step in the design of a novel immunomodulatory agent applicable to confer protection against fungal diseases

Abstract

Our group has regularly investigated the recognition of glycans on host cells by pathogen lectins; we have also studied the biological responses triggered by such recognition. Our team has focused on particular lectins: (i) TgMIC1 and TgMIC4 - proteins secreted by micronemas of the protozoan Toxoplasma gondii that recognize glycans bearing sialic acid and beta-galactose as terminal residues, respectively; (ii) paracoccin, proteins of the surface of Paracoccidioides brasiliensis yeasts that recognize N-acetylglucosamine. In these cases, we have isolated the proteins by affinity chromatography on columns of their specific sugar; we have also characterized the structure and biological properties of the native forms of each of these lectins. The relevance of the activities performed by these proteins have motivated us to clone the gene codifying each lectin and express it heterologously. We have characterized the resulting recombinant proteins in terms of their ability to reproduce the properties of the corresponding native lectin. Functional studies revealed that the lectins derived from T. gondii and P. brasiliensis play relevant roles in pathogen biology and affect host cell immunity. We have examined the recognition involved in the induction of these effects, the identification of molecules containing the recognition target, the cell signaling triggered by this recognition, the cellular responses stemming from cell activation, and the consequent production of immunological modulators as well as the resistance conferred by these processes. (AU)