Human neutrophil Siglec-9 is a lectin that recognizes sialic acids (Sias) via an amino-terminal V-set Ig domain and possesses tyrosine-based inhibitory motifs in its cytoplasmic tail. We hypothesized that Siglec-9 recognizes host Sias as "self," including in cis interactions with Sias on the neutrophil's own surface, thereby dampening unwanted neutrophil reactivity. Here we show that neutrophils presented with immobilized multimerized Sia␣2-3Gal1-4GlcNAc units engage them in trans via Siglec-9. The sialylated capsular polysaccharide of group B Streptococcus (GBS) also presents terminal Sia␣2-3Gal1-4GlcNAc units, and similarly engages neutrophil Siglec-9, dampening neutrophil responses in a Sia-and Siglec-9-dependent manner. Reduction in the neutrophil oxidative burst, diminished formation of neutrophil extracellular DNA traps, and increased bacterial survival are also facilitated by GBS sialylated capsular polysaccharide interactions with Siglec-9. Thus, GBS can impair neutrophil defense functions by coopting a host inhibitory receptor via sialoglycan molecular mimicry, a novel mechanism of bacterial immune evasion. (Blood. 2009; 113:3333-3336)
IntroductionAlthough antimicrobial properties of vertebrate innate immune cells are extensively studied, less is understood about mechanisms dampening inflammatory responses. Such negative regulatory systems can be subverted by microbes. Of relevant interest is the "molecular mimicry" of mammalian sialic acid (Sia)-terminated sialoglycans by microbes that are obligate commensals or potential pathogens of humans. 1 Surface Sia expression can blunt alternative pathway complement activation and reduce immunogenicity. 1 However, this may not fully explain convergent bacterial evolution of near-perfect mimicry of vertebrate sialoglycans. For example, the human-specific commensal/pathogen group B Streptococcus (GBS) has a capsular polysaccharide (CPS) that displays the structure Sia␣2-3Gal1-4GlcNAc, 2 a sequence identical to one common at termini of human glycoproteins.Sia-recognizing immunoglobulin superfamily lectins (Siglecs) are type I transmembrane proteins expressed on immune cells. 3,4 The rapidly evolving subgroup of CD33-related Siglecs (CD33rSiglecs) are postulated (but not proven) to negatively regulate inflammatory responses by recognizing host sialoglycans. 3 Many CD33rSiglecs have conserved cytoplasmic tyrosine-based motifs, comprising a membrane-proximal immunoreceptor tyrosinebased inhibitory motif (ITIM) and a membrane-distal ITIM-like motif. 3,4 The wide expression of host Sias and the prominence of cognate ITIM-bearing CD33rSiglecs on immune cells suggest that they may function in "self"-recognition, dampening innate immune responses to prevent autoreactivity. 3 The functional outcome of CD33rSiglec binding to sialylated ligands remains poorly understood. Cross-linking antibodies and/or Siglec transfection into Siglec-deficient cell lines has demonstrated the importance of the ITIM and ITIM-like motifs for inhibiting cellular activation and proliferation, ...
Background: Mucus degradation is hypothesized to be important in bacterial vaginosis (BV), but mechanisms require investigation. Results: We characterize a Gardnerella vaginalis pathway that performs digestion/catabolism of mucus sialoglycans. Conclusion: G. vaginalis participates in mucosal sialic acid depletion in BV. Significance: G. vaginalis is the first example of a BV-associated organism that recapitulates a measurable clinical phenotype of mucus degradation in an animal model.
Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of Ϸ1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the ''unique'' Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars. legionaminic acid ͉ phylogeny ͉ pseudaminic acid ͉ neuraminic acid ͉ biosynthetic pathway
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.