Sialic acids (Sias) are negatively-charged sugars on cell surface or secreted molecules. Several Sia biological roles involve Sia-recognizing receptors called Siglecs (Sia-recognizing Ig-like lectins). Many ofthe CD33-related subset of Siglecs (CD33rSiglecs) on innate immune cells appear to recognize host Sias as "self, dampening inflammatory reactivity via cytosolic Immunoreceptor Tyrosine-Based Inhibitory Motifs (ITIMs). However, bacteria expressing Sias can "hijack" these Siglecs, to suppress innate immune responses. Another subset of CD33rSiglecs lack ITIMs and instead recruit the Immunoreceptor Tyrosine- Based Activatory Motifs (ITAMs) of DAP-12. The functions of activatory Siglecs are unknown. Also unexplained are CD33rSiglecs that undergo lineage-specific mutations of an amino-terminal V-set domain critical Arg residue required for Sia recognition. The overall hypothesis is that the activatory and Arg-mutated versions of CD33rSiglecs represent evolutionary adjustments of inflammatory responses of innate immune cells, faced with pathogens expressing surface Sias that can subvert inhibitory Siglecs. As with several Siglec mutations, many of these Sia-expressing pathogens are human-specific. Some questions can be addressed by comparisons of innate immune cells from human and great ape blood. However, given practical, fiscal and ethical issues, we will,use transgenic mice as models. On a more fundamental level, these studies will address the general significance of mammalian activatory and Arg-mutated Siglecs in modulating the "set-state" of the myelomonocytic cell innate immune response, and the inflammatory response to bacterial pathogens bearing Sias.
Specific aims i nclude: generating and studying mice with transgenic expression of native or arginine-mutated human Siglec-9 or with combinations of activatory and/or inhibitory forms of Siglec-E on neutrophils, monocytes and macrophages;comparing human and chimpanzee innate immune cells with different combinations of activatory/lnhibitory and or Arg-mutated forms of Siglec-5 and Siglec-14;and finally, comparing the interacfions of innate immune cells from the above studies with certain pathogenic bacteria that express sialic acid mimics of Siglec ligands.
Individual humans seem to vary widely in their immediate responses to inflammatory or infectious insults. We have discovered that humans also vary greatly in certain genes called SIGLECs that are expressed on the white blood cell types involved in such responses. In order to eventually understand the significance of this variafion for humans in health and disease we need to first model and study these variafions in mice.
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