title: Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire.
abstract: Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition.
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Yik Andy
authors.initials: YA
authors.lastname: Yeung
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Foletti
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Abdiche
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strop
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Glanville
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Pitts
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lindquist
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Purnima D
authors.initials: PD
authors.lastname: Sundar
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Sirota
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Adela
authors.initials: A
authors.lastname: Hasa-Moreno
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Pham
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Jody
authors.initials: J
authors.lastname: Melton Witt
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Ni
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Jaume
authors.initials: J
authors.lastname: Pons
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Shelton
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Rajpal
authors.affiliation: Rinat R&D, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Chaparro-Riggers
mesh_terms: D000907:Antibodies, Bacterial / Q000276:immunology*; D057134:Antibodies, Neutralizing; D001402:B-Lymphocytes; D001426:Bacterial Proteins / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008958:Models, Molecular; D011487:Protein Conformation; D000072417:Protein Domains; D062085:RNA, Long Noncoding; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology*; D013211:Staphylococcus aureus; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; C557041:MALAT1 long non-coding RNA, human; C577276:NEAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D037521:Virulence Factors