Sialic acids (Sias) are found to the outermost ends of sugar chains of most cell surface molecules. Their two most common linkages to underlying sugar chains are alpha2-3 or 2-6 to a galactose unit. The most common Sia is N-acetylneuraminic acid (Neu5Ac), and two common modifications are 9- O-acetylation and an 5-Nglycolyl group instead of the usual 5-N-acetyl group. Siglecs (sialic acid-binding Ig superfamily lectins) are a family of cell surface proteins that recognize Sias via their first Ig V-set domains. Sia recognition by Siglecs can be affected by the linkage of the Sia to the underlying sugar chain as well as by the above-mentioned modifications. Siglec recognition of Sias is partially or completely dependent on a conserved """"""""critical arginine"""""""" residue in the amino-terminal V-set domain. The Sia binding sites of most Siglecs are """"""""masked"""""""" by interactions with Sia residues on the same cell surface, and can be unmasked during activation. The CD33-related Siglecs are selectively expressed on certain blood cell types, and have tyrosine-based signaling motifs in their cytosolic tails. The primary functions of most Siglecs is unknown. We hypothesize that linkage differences and/or modifications of Sias on mature cells of the myelomonocytic lineage (neutrophils, monocytes and macrophages) cells can regulate the levels and signaling of Siglecs in bone marrow development and/or in innate immunity. We propose that Siglecs regulate cellular responses to microorganisms that express sialidases and/or their own cell surface sialic acids by acting as """"""""biological sensors of sialylation states"""""""" of both self and non-self. To pursue these hypotheses, we will (a) generate and characterize mice with single or double mutations in Siglec-3/CD33 and Siglec-F the two major Siglecs on cells of the myelomonocytic lineage; (b) define the unmasking and signaling state of myelomonocytic Siglecs in mice with combinations of deficiencies in the ST3Gal I sialyltransferases; (c) generate and characterize mice with altered expression of modified sialic acids in cells of the myelomonocytic lineage; and, (d) study the consequences of the above genetic alterations on the responses of neutrophils and monocytes to defined microbes expressing sialidases or sialic acids. These studies will test if these Siglecs on myelomonocytic cells act as biologic sensors of sialylation states, and if the genetic alterations in mice result in pathologically altered responses to the microbes.
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