title: Rapid evolution of binding specificities and expression patterns of inhibitory CD33-related Siglecs in primates.
abstract: Siglecs are sialic acid-binding Ig-like lectins that recognize sialoglycans via amino-terminal V-set domains. CD33-related Siglecs (CD33rSiglecs) on innate immune cells recognize endogenous sialoglycans as "self-associated molecular patterns" (SAMPs), dampening immune responses via cytosolic immunoreceptor tyrosine-based inhibition motifs that recruit tyrosine phosphatases. However, sialic acid-expressing pathogens subvert this mechanism through molecular mimicry. Meanwhile, endogenous host SAMPs must continually evolve to evade other pathogens that exploit sialic acids as invasion targets. We hypothesized that these opposing selection forces have accelerated CD33rSiglec evolution. We address this by comparative analysis of major CD33rSiglec (Siglec-3, Siglec-5, and Siglec-9) orthologs in humans, chimpanzees, and baboons. Recombinant soluble molecules displaying ligand-binding domains show marked quantitative and qualitative interspecies differences in interactions with strains of the sialylated pathogen, group B Streptococcus, and with sialoglycans presented as gangliosides or in the form of sialoglycan microarrays, including variations such as N-glycolyl and O-acetyl groups. Primate Siglecs also show quantitative and qualitative intra- and interspecies variations in expression patterns on leukocytes, both in circulation and in tissues. Taken together our data explain why the CD33rSiglec-encoding gene cluster is undergoing rapid evolution via multiple mechanisms, driven by the need to maintain self-recognition by innate immune cells, while escaping 2 distinct mechanisms of pathogen subversion.
authors.affiliation: 39500 Gilman Dr., University of California at San Diego, La Jolla, CA 92093-0687, USA. a1varki@ucsd.edu.
authors.forename: Vered
authors.initials: V
authors.lastname: Padler-Karavani
authors.forename: Nancy
authors.initials: N
authors.lastname: Hurtado-Ziola
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Chang
authors.forename: Justin L
authors.initials: JL
authors.lastname: Sonnenburg
authors.forename: Arash
authors.initials: A
authors.lastname: Ronaghy
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.forename: Andrea
authors.initials: A
authors.lastname: Verhagen
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001483:Base Sequence; D017931:DNA Primers; D007150:Immunohistochemistry; D011323:Primates / Q000276:immunology*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000276:immunology*
chemical_list: D017931:DNA Primers; D063268:Sialic Acid Binding Ig-like Lectin 3; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
keywords: N-acetylneuraminic acid; N-glycolylneuraminic acid; innate immunity; sialic acids