title: Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation.
abstract: Inhibitory CD33-related Siglec receptors regulate immune cell activation upon engaging ubiquitous sialic acids (Sias) on host cell surface glycans. Through molecular mimicry, Sia-expressing pathogen group B Streptococcus binds inhibitory human Siglec-9 (hSiglec-9) to blunt neutrophil activation and promote bacterial survival. We unexpectedly discovered that hSiglec-9 also specifically binds high molecular weight hyaluronan (HMW-HA), another ubiquitous host glycan, through a region of its terminal Ig-like V-set domain distinct from the Sia-binding site. HMW-HA recognition by hSiglec-9 limited neutrophil extracellular trap (NET) formation, oxidative burst, and apoptosis, defining HMW-HA as a regulator of neutrophil activation. However, the pathogen group A Streptococcus (GAS) expresses a HMW-HA capsule that engages hSiglec-9, blocking NET formation and oxidative burst, thereby promoting bacterial survival. Thus, a single inhibitory lectin receptor detects two distinct glycan "self-associated molecular patterns" to maintain neutrophil homeostasis, and two leading human bacterial pathogens have independently evolved molecular mimicry to exploit this immunoregulatory mechanism.
  
  
  CONCLUSIONS
  HMW-HA is the first example of a non-sialic acid containing glycan to be recognized by CD33-related Siglecs. HMW-HA engagement of hSiglec-9 attenuates neutrophil activation. Group A Streptococcus exploits hSiglec-9 recognition via its polysaccharide HMW-HA capsule to subvert neutrophil killing.
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Pediatrics, UC San Diego, La Jolla, CA, USA.|Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico.
authors.forename: Ismael
authors.initials: I
authors.lastname: Secundino
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA.
authors.forename: Anel
authors.initials: A
authors.lastname: Lizcano
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Pediatrics, UC San Diego, La Jolla, CA, USA.|Faculty of Medicine, Lund University, Lund, Sweden.
authors.forename: K Markus
authors.initials: KM
authors.lastname: Roupé
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, UC San Diego, La Jolla, CA, USA.|Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.affiliation: Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
authors.forename: S Raza
authors.initials: SR
authors.lastname: Ali
authors.affiliation: Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Dahesh
authors.affiliation: Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
authors.forename: Lenah K
authors.initials: LK
authors.lastname: Amayreh
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.|Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Henningham
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA. a1varki@ucsd.edu.|Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA. a1varki@ucsd.edu.|Department of Medicine, UC San Diego, La Jolla, CA, USA. a1varki@ucsd.edu.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.affiliation: Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA. vnizet@ucsd.edu.|Department of Pediatrics, UC San Diego, La Jolla, CA, USA. vnizet@ucsd.edu.|Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA. vnizet@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001419:Bacteria / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D065206:Extracellular Traps / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D007113:Immunity, Innate; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D008970:Molecular Weight; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins; D016897:Respiratory Burst / Q000276:immunology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013291:Streptococcus / Q000502:physiology
chemical_list: D015703:Antigens, CD; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D006820:Hyaluronic Acid
keywords: CD33-related Siglecs; Group A Streptococcus (GAS); Hyaluronan; Neutrophils