title: The Group B Streptococcus-Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways.
abstract: The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen.
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, 27100 Pavia, Italy; and.
authors.forename: Giampiero
authors.identifier: http://orcid.org/0000-0002-7069-8155
authors.initials: G
authors.lastname: Pietrocola
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, 27100 Pavia, Italy; and.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Rindi
authors.affiliation: GSK Vaccines S.r.l., 53100 Siena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rosini
authors.affiliation: GSK Vaccines S.r.l., 53100 Siena, Italy.
authors.forename: Scilla
authors.initials: S
authors.lastname: Buccato
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, 27100 Pavia, Italy; and immaculada.x.margarit-y-ros@gsk.com pspeziale@unipv.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Speziale
authors.affiliation: GSK Vaccines S.r.l., 53100 Siena, Italy immaculada.x.margarit-y-ros@gsk.com pspeziale@unipv.it.
authors.forename: Immaculada
authors.initials: I
authors.lastname: Margarit
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000096:biosynthesis / Q000276:immunology; D015935:Complement C4b / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000276:immunology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013292:Streptococcus agalactiae / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D011994:Recombinant Proteins; D003179:Complement C3b; D015935:Complement C4b