My laboratory is investigating carbohydrate-modifying enzymes that influence the activity of cells of the immune system by modulating the sialic acid content of surface glycoproteins and glycolipids. Sialidases comprise a family of glycosidases that remove terminal sialyl residues from glycoconjugates. Although four genetically-distinct sialidases have been identified in mammalian cells, we have found that only three of these sialidases, lysosomal Neu1 and Neu4 and plasma membrane-associated Neu3, are expressed in human peripheral blood mononuclear cells (PBMCs). Our laboratory has shown that activation and/or differentiation of PBMCs results in changes in the expression of some of these enzymes, with a consequent alteration in the content of cell surface sialic acid. The intracellular location of Neu1 and Neu3 in these cells appears to be more complex than originally suggested, and we have shown that both Neu1 and Neu3 are present on the cell surface. Thus, Neu1 and Neu3 can influence the immune function of PBMCs by desialylating glycoconjugates on the resident cell surface, on the surface of neighboring cells, and on ligands and microbes in the extracellular milieu. We have shown that Neu1 and/or Neu3 activity in these cells increases their permissivity for infection with HIV-1 and their production of cytokines (IL12, TNFa, IL6, IFNg) in response to lipopolysaccharide (LPS). The mechanisms underlying these findings are currently under investigation. One goal of this work is to determine whether pharmacologic sialidase inhibitors or monoclonal antibodies against Neu1 or Neu3 have therapeutic value in infectious and inflammatory conditions.
Stamatos, N.M., Curreli, S., Zella, D. and A. S. Cross. 2004. Desialylation of glycoconjugates on the surface of monocytes activates the extracellular signal-related kinases ERK 1/2 and results in enhanced production of specific cytokines. J. Leuk. Biol. 75:307-313.
Stamatos, N. M., Liang F., Nan X., Landry K., Cross A. S., Wang L. X. and A. V. Pshezhetsky. 2005. Differential expression of endogenous sialidases of human monocytes during cellular differentiation into macrophages. FEBS Journal, 272:2545-2556.