title: The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design.
abstract: Group A Streptococcus (GAS) is a leading cause of infection-related mortality in humans. All GAS serotypes express the Lancefield group A carbohydrate (GAC), comprising a polyrhamnose backbone with an immunodominant N-acetylglucosamine (GlcNAc) side chain, which is the basis of rapid diagnostic tests. No biological function has been attributed to this conserved antigen. Here we identify and characterize the GAC biosynthesis genes, gacA through gacL. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37. Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization. Thus, the Lancefield antigen plays a functional role in GAS pathogenesis, and a deeper understanding of this unique polysaccharide has implications for vaccine development.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.|Medical Microbiology, University Medical Center Utrecht,3584 CX Utrecht, The Netherlands.
authors.forename: Nina M
authors.initials: NM
authors.lastname: van Sorge
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.|Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland,QLD 4072, Australia.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kuipers
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Henningham
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.|Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University,11562 Cairo, Egypt.
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Aziz
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Kasirer-Friede
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Lin
authors.affiliation: Medical Microbiology, University Medical Center Utrecht,3584 CX Utrecht, The Netherlands.
authors.forename: Evelien T M
authors.initials: ETM
authors.lastname: Berends
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland,QLD 4072, Australia.|The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, CB10 1SA,United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davies
authors.affiliation: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, CB10 1SA,United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Dahesh
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Shaw
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gin
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Cunningham
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Merriman
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, 14476 Potsdam, Germany.|Freie Universität Berlin, Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hütter
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, 14476 Potsdam, Germany.|Freie Universität Berlin, Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.affiliation: Medical Microbiology, University Medical Center Utrecht,3584 CX Utrecht, The Netherlands.
authors.forename: Suzan H M
authors.initials: SHM
authors.lastname: Rooijakkers
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Malley
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland,QLD 4072, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schlievert
authors.affiliation: Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Biswa
authors.initials: B
authors.lastname: Choudhury
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.|Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000117:Acetylglucosamine / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins / Q000235:genetics; D002241:Carbohydrates / Q000276:immunology; D054804:Cathelicidins / Q000494:pharmacology; D000939:Epitopes; D005260:Female; D016695:Glycosyltransferases / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008815:Mice, Inbred Strains; D016296:Mutagenesis; D009504:Neutrophils / Q000382:microbiology; D011817:Rabbits; D013290:Streptococcal Infections / Q000276:immunology / Q000821:virology*; D022541:Streptococcal Vaccines / Q000235:genetics / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D002241:Carbohydrates; D054804:Cathelicidins; D000939:Epitopes; C091100:GacA protein, Bacteria; D022541:Streptococcal Vaccines; D037521:Virulence Factors; D016695:Glycosyltransferases; D000117:Acetylglucosamine