Human-Specific Changes in the Biology of Siglecs and their Relevance for Host–Microbe Interactions

Flavio Schwarz, Victor Nizet and Ajit Varki

Siglecs are cell surface receptors of innate immune cells that bind sialic acids on a variety of glycoconjugates. Many of the CD33-related subset of Siglecs (CD33rSiglecs) recognize host sialic acids and reduce inflammatory reactivity by signaling via their cytosolic Immunoreceptor Tyrosine-Based Inhibitory Motifs (ITIMs). Thus, CD33rSiglec/host ligand interactions appear to regulate the steady state level of immune responses upon sensing of "self-associated molecular patterns". However, some CD33rSiglecs have undergone mutations of a arginine residue required for sialic acid binding. Moreover, a subset of CD33rSiglecs lack ITIMs and instead recruit the Immunoreceptor Tyrosine-Based Activating Motifs (ITAMs) of DAP12. The overall hypothesis arising from these observations is that the mutated and activating versions of CD33rSiglecs allow evolutionary adjustments of inflammatory responses of innate immune cells, especially in the face of pathogens expressing surface sialic acids that can subvert inhibitory Siglecs. In this respect, Siglec-5/-14 and Siglec-11/-16 are paired receptors with virtually indistinguishable sialic acid binding properties, but possessing intracellular domains capable of inducing opposing signals. We have found that Group B Streptococcus binds to Siglec-5 to inhibit immune responses. Similarly, Escherichia coli K1, an agent of meningitis, produces a capsule that enables the bacterium to interact with Siglec-11, to dampen phagocytosis. By contrast, interaction of the same bacteria with activating Siglec-14 and Siglec-16 enhances bacterial killing. Thus, the high frequency of SIGLEC gene changes in the human lineage may be a reflection of the competing demands of self-recognition and pathogen response, and may in turn affect susceptibility to other diseases affected by inflammation.